Evolutionary divergence and functions of the human interleukin (IL) gene family

Abstract

Cytokines play a very important role in nearly all aspects of inflammation and immunity. The term 'interleukin' (IL) has been used to describe a group of cytokines with complex immunomodulatory functions -- including cell proliferation, maturation, migration and adhesion. These cytokines also play an important role in immune cell differentiation and activation. Determining the exact function of a particular cytokine is complicated by the influence of the producing cell type, the responding cell type and the phase of the immune response. ILs can also have pro- and anti-inflammatory effects, further complicating their characterisation. These molecules are under constant pressure to evolve due to continual competition between the host's immune system and infecting organisms; as such, ILs have undergone significant evolution. This has resulted in little amino acid conservation between orthologous proteins, which further complicates the gene family organisation. Within the literature there are a number of overlapping nomenclature and classification systems derived from biological function, receptor-binding properties and originating cell type. Determining evolutionary relationships between ILs therefore can be confusing. More recently, crystallographic data and the identification of common structural motifs have led to a more accurate classification system. To date, the known ILs can be divided into four major groups based on distinguishing structural features. These groups include the genes encoding the IL1-like cytokines, the class I helical cytokines (IL4-like, γ-chain and IL6/12-like), the class II helical cytokines (IL10-like and IL28-like) and the IL17-like cytokines. In addition, there are a number of ILs that do not fit into any of the above groups, due either to their unique structural features or lack of structural information. This suggests that the gene family organisation may be subject to further change in the near future.

making its classification very difficult. Further studies have shown that IL32 is also released from monocytes and epithelial cells [176, 177]. It stimulates the release of pro-inflammatory cytokines, including IL1B, IL6, IL8, TNF and macrophage inflammatory protein 2 (MIP2) [176]. The signalling pathways for IL32 have yet to be fully characterised; however, studies have shown that they involve the NF-?B and p38 mitogen-activated protein kinase pathways, which are commonly associated with inflammation [178]. A number of diseases associated with IL32 expression, including inflammatory bowel disease, myelodysplastic syndrome and HIV infection [179-181]. IL32 lacks significant amino acid identity (< 15 per cent) with the other cytokines listed in Table 1. Furthermore, BLAST analyses failed to identify any significantly homologous proteins.

IL34 was identified in 2008 by Lin et al [182]. It binds to the homodimeric CSF1 receptor (CSFR1), which also binds CSF1 [182]. CSF1 is a cytokine that controls the division, differentiation and function of monocytes, macrophages and osteoblasts [183]. Similar to CSF1, human IL34 has been found to function as a homodimer [182]. Furthermore, modelling of both IL34 and CSF1 identified a stacked 'four-helix bundle' structure [184]. The CSF1 monomer is structurally very similar to CSF2, a short-chain class I helical cytokine [185]. There is a high likelihood that both CSF1 and IL34 are evolutionarily related to the class I helical cytokines. BLAST analysis of the IL34 peptide sequence failed to identify any significantly homologous proteins within the human genome. Pairwise alignments revealed that IL34 shares 19 per cent sequence identity with OSM and CNTF, both of which are long-chain class I helical cyto-kines. Sequence homology between other ILs and cytokines was not significant (ie < 15 per cent).

Conclusions

To date, the human IL gene family contains 55 known IL and IL-related genes. The majority of ILs can be classified into seven distinct groups and subgroups using characteristic structural features. These groups include genes encoding the IL1-like cytokines, the class I helical cytokines (IL4-like, ?-chain and IL6/12-like), the class II helical cytokines (IL10-like and IL28-like) and the IL17-like cytokines. Because evolutionary divergence occurs so rapidly in these genes, it is impossible in many cases to assign a member to a specific 'gene family' or 'gene subfamily'; therefore, structural analysis has become the principle approach for classifying. A number of 'interleukin' genes currently lack the structural information required for classification. It is therefore likely that these groups will expand as crystallisation data and structural analyses become available.

Declarations

Acknowledgements

We would like to thank our colleagues for valuable discussion and critical review of this manuscript. This work was supported, in part, by the following NIH grants: R01 EY17963 (V.V.), R21 AA017754 (V.V.), F31 AA018248 (C.B.) and P30 ES06096 (D.W.N.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

References

Commins SP, Borish L, Steinke JW: Immunologic messenger molecules: Cytokines. interferons, and chemokines. J Allergy Clin Immunol. 2010, 125: S53-S72. 10.1016/j.jaci.2009.07.008.Google Scholar

Aarden LA, Brunner TK, Cerottini JC, Dayer JM, et al: Revised nomenclature for antigen-non-specific T cell proliferation and helper factors. J Immunol. 1979, 123: 2928-2929.Google Scholar

Liles WC, Van Voorhis WC: Review: Nomenclature and biologic significance of cytokines involved in inflammation and the host immune response. J Infect Dis. 1995, 172: 1573-1580. 10.1093/infdis/172.6.1573.Google Scholar

Anon: Nomenclature for secreted regulatory proteins of the immune system (interleukins). WHO-IUIS Nomenclature Subcommittee on Interleukin Designation. Bull World Health Organ. 1991, 69: 483-486.Google Scholar

Anon: Nomenclature for secreted regulatory proteins of the immune system (interleukins): Update. IUIS/WHO Nomenclature Committee. Bull World Health Organ. 1994, 72: 811-812.Google Scholar

Anon: Interleukin 16 (IL-16). IUIS/WHO Standing Committee on Interleukin Designation. Bull World Health Organ. 1996, 74: 451-452.Google Scholar

Anon: Nomenclature for secreted regulatory proteins of the immune system (interleukins): Update. IUIS/WHO Standing Committee on Interleukin Designation. Bull World Health Organ. 1997, 75: 175-Google Scholar

Sims JE, Nicklin MJ, Bazan JF, Barton JL, et al: A new nomenclature for IL-1-family genes. Trends Immunol. 2001, 22: 536-537. 10.1016/S1471-4906(01)02040-3.Google Scholar

Boulay JL, Paul WE: The interleukin-4 family of lym-phokines. Curr Opin Immunol. 1992, 4: 294-298. 10.1016/0952-7915(92)90079-T.Google Scholar

Veerapandian B, Gilliland GL, Raag R, Svensson AL, et al: Functional implications of interleukin-1 beta based on the three-dimensional structure. Proteins. 1992, 12: 10-23. 10.1002/prot.340120103.Google Scholar

Priestle JP, Schar HP, Grutter MG: Crystallographic refinement of interleukin 1 beta at 2.0 A resolution. Proc Natl Acad Sci USA. 1989, 86: 9667-9671. 10.1073/pnas.86.24.9667.Google Scholar

Vigers GP, Caffes P, Evans RJ, Thompson RC, et al: X-ray structure of interleukin-1 receptor antagonist at 2.0-A resolution. J Biol Chem. 1994, 269: 12874-12879.Google Scholar

Graves BJ, Hatada MH, Hendrickson WA, Miller JK, et al: Structure of interleukin 1 alpha at 2.7-A resolution. Biochemistry. 1990, 29: 2679-2684. 10.1021/bi00463a009.Google Scholar

Boulay JL, O'Shea JJ, Paul WE: Molecular phylogeny within type I cytokines and their cognate receptors. Immunity. 2003, 19: 159-163. 10.1016/S1074-7613(03)00211-5.Google Scholar

Ealick SE, Cook WJ, Vijay-Kumar S, Carson M, et al: Three-dimensional structure of recombinant human interferongamma. Science. 1991, 252: 698-702. 10.1126/science.1902591.Google Scholar

Zdanov A, Schalk-Hihi C, Gustchina A, Tsang M, et al: Crystal structure of interleukin-10 reveals the functional dimer with an unexpected topological similarity to interferon gamma. Structure. 1995, 3: 591-601. 10.1016/S0969-2126(01)00193-9.Google Scholar

Kotenko SV: The family of IL-10-related cytokines and their receptors: Related, but to what extent?. Cytokine Growth Factor Rev. 2002, 13: 223-240. 10.1016/S1359-6101(02)00012-6.Google Scholar

Sheppard P, Kindsvogel W, Xu W, Henderson K, et al: IL-28, IL-29 and their class II cytokine receptor IL-28R. Nat Immunol. 2003, 4: 63-68. 10.1038/ni873.Google Scholar

Witte K, Witte E, Sabat R, Wolk K: IL-28A, IL-28B, and IL-29: Promising cytokines with type I interferon-like properties. Cytokine Growth Factor Rev. 2010, 21: 237-251. 10.1016/j.cytogfr.2010.04.002.Google Scholar

Hymowitz SG, Filvaroff EH, Yin JP, Lee J, et al: IL-17s adopt a cystine knot fold: structure and activity of a novel cytokine IL-17F, and implications for receptor binding. EMBO J. 2001, 20: 5332-5341. 10.1093/emboj/20.19.5332.Google Scholar

McDonald NQ, Hendrickson WA: A structural superfamily of growth factors containing a cystine knot motif. Cell. 1993, 73: 421-424. 10.1016/0092-8674(93)90127-C.Google Scholar

Hurst LD, Smith NG: Do essential genes evolve slowly?. Curr Biol. 1999, 9: 747-750. 10.1016/S0960-9822(99)80334-0.Google Scholar

Scapigliati G, Buonocore F, Mazzini M: Biological activity of cytokines: An evolutionary perspective. Curr Pharm Des. 2006, 12: 3071-3081. 10.2174/138161206777947489.Google Scholar

Luporini P, Vallesi A, Miceli C, Bradshaw RA: Ciliate pheromones as early growth factors and cytokines. Ann NY Acad Sci. 1994, 712: 195-205. 10.1111/j.1749-6632.1994.tb33573.x.Google Scholar

Vallesi A, Giuli G, Ghiara P, Scapigliati G, et al: Structure-function relationships of pheromones of the ciliate Euplotes raikovi with mammalian growth factors: Cross-reactivity between Er-1 and interleukin-2 systems. Exp Cell Res. 1998, 241: 253-259. 10.1006/excr.1998.4056.Google Scholar

Bingulac-Popovic J, Figueroa F, Sato A, Talbot WS, et al: Mapping of mhc class I and class II regions to different linkage groups in the zebrafish Danio rerio. Immunogenetics. 1997, 46: 129-134. 10.1007/s002510050251.Google Scholar

Nicklin MJ, Weith A, Duff GW: A physical map of the region encompassing the human interleukin-1 alpha. interleukin-1 beta, and interleukin-1 receptor antagonist genes. Genomics. 1994, 19: 382-384. 10.1006/geno.1994.1076.Google Scholar

Dunn E, Sims JE, Nicklin MJ, O'Neill LA: Annotating genes with potential roles in the immune system: Six new members of the IL-1 family. Trends Immunol. 2001, 22: 533-536. 10.1016/S1471-4906(01)02034-8.Google Scholar

Takahashi M, Yoshida MC, Satoh H, Hilgers J, et al: Chromosomal mapping of the mouse IL-4 and human IL-5 genes. Genomics. 1989, 4: 47-52. 10.1016/0888-7543(89)90313-3.Google Scholar

Yang YC, Kovacic S, Kriz R, Wolf S, et al: The human genes for GM-CSF and IL 3 are closely linked in tandem on chromosome 5. Blood. 1988, 71: 958-961.Google Scholar

van Leeuwen BH, Martinson ME, Webb GC, Young IG: Molecular organization of the cytokine gene cluster. involving the human IL-3, IL-4, IL-5, and GM-CSF genes, on human chromosome 5. Blood. 1989, 73: 1142-1148.Google Scholar

Sanderson CJ, Campbell HD, Young IG: Molecular and cellular biology of eosinophil differentiation factor (interleukin-5) and its effects on human and mouse B cells. Immunol Rev. 1988, 102: 29-50. 10.1111/j.1600-065X.1988.tb00740.x.Google Scholar

Lee JS, Campbell HD, Kozak CA, Young IG: The IL-4 and IL-5 genes are closely linked and are part of a cytokine gene cluster on mouse chromosome 11. Somat Cell Mol Genet. 1989, 15: 143-152. 10.1007/BF01535075.Google Scholar

Ryan AW, Thornton JM, Brophy K, Daly JS, et al: Chromosome 5q candidate genes in coeliac disease: Genetic variation at IL4, IL5, IL9, IL13, IL17B and NR3C1. Tissue Antigens. 2005, 65: 150-155. 10.1111/j.1399-0039.2005.00354.x.Google Scholar

Webb GC, Lee JS, Campbell HD, Young IG: The genes for interleukins 3 and 5 map to the same locus on mouse chromosome 11. Cytogenet Cell Genet. 1989, 50: 107-110. 10.1159/000132734.Google Scholar

Giovannini M, Djabali M, McElligott D, Selleri L, et al: Tandem linkage of genes coding for leukemia inhibitory factor (LIF) and oncostatin M (OSM) on human chromosome 22. Cytogenet Cell Genet. 1993, 64: 240-244. 10.1159/000133586.Google Scholar

Jeffery E, Price V, Gearing DP: Close proximity of the genes for leukemia inhibitory factor and oncostatin M. Cytokine. 1993, 5: 107-111. 10.1016/1043-4666(93)90048-A.Google Scholar

Oral HB, Kotenko SV, Yilmaz M, Mani O, et al: Regulation of T cells and cytokines by the interleukin-10 (IL-10)-family cytokines IL-19, IL-20, IL-22, IL-24 and IL-26. Eur J Immunol. 2006, 36: 380-388. 10.1002/eji.200425523.Google Scholar

Uze G, Monneron D: IL-28 and IL-29: Newcomers to the interferon family. Biochimie. 2007, 89: 729-734. 10.1016/j.biochi.2007.01.008.Google Scholar

Starnes T, Robertson MJ, Sledge G, Kelich S, et al: Cutting edge: IL-17F. a novel cytokine selectively expressed in activated T cells and monocytes, regulates angiogenesis and endothelial cell cytokine production. J Immunol. 2001, 167: 4137-4140.Google Scholar

Moseley TA, Haudenschild DP, Rose L, Reddi AH: Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev. 2003, 14: 155-174. 10.1016/S1359-6101(03)00002-9.Google Scholar

Fryxell KJ: The coevolution of gene family trees. Trends Genet. 1996, 12: 364-369.Google Scholar

Ahuja SK, Ozcelik T, Milatovitch A, Francke U, et al: Molecular evolution of the human interleukin-8 receptor gene cluster. Nat Genet. 1992, 2: 31-36. 10.1038/ng0992-31.Google Scholar

Kohu K, Yamabe E, Matsuzawa A, Onda D, et al: Comparison of 30 immunity-related genes from the common marmoset with orthologues from human and mouse. Tohoku J Exp Med. 2008, 215: 167-180. 10.1620/tjem.215.167.Google Scholar

Kaiser P, Rothwell L, Avery S, Balu S: Evolution of the interleukins. Dev Comp Immunol. 2004, 28: 375-394. 10.1016/j.dci.2003.09.004.Google Scholar

Liongue C, Ward AC: Evolution of class I cytokine receptors. BMC Evol Biol. 2007, 7: 120-10.1186/1471-2148-7-120.Google Scholar

Nicklin MJ, Barton JL, Nguyen M, FitzGerald MG, et al: A sequence-based map of the nine genes of the human interleukin-1 cluster. Genomics. 2002, 79: 718-725. 10.1006/geno.2002.6751.Google Scholar

Arend WP, Palmer G, Gabay C: IL-1. IL-18, and IL-33 families of cytokines. Immunol Rev. 2008, 223: 20-38. 10.1111/j.1600-065X.2008.00624.x.Google Scholar

Barksby HE, Lea SR, Preshaw PM, Taylor JJ: The expanding family of interleukin-1 cytokines and their role in destructive inflammatory disorders. Clin Exp Immunol. 2007, 149: 217-225. 10.1111/j.1365-2249.2007.03441.x.Google Scholar

Gabay C, Lamacchia C, Palmer G: IL-1 pathways in inflammation and human diseases. Nat Rev Rheumatol. 2010, 6: 232-241. 10.1038/nrrheum.2010.4.Google Scholar

Weber A, Wasiliew P, Kracht M: Interleukin-1 (IL-1) pathway. Sci Signal. 2010, 3: cm1-10.1126/scisignal.3105cm1.Google Scholar

Allantaz F, Chaussabel D, Stichweh D, Bennett L, et al: Blood leukocyte microarrays to diagnose systemic onset juvenile idiopathic arthritis and follow the response to IL-1 blockade. J Exp Med. 2007, 204: 2131-2144. 10.1084/jem.20070070.Google Scholar

Vincenti MP, Brinckerhoff CE: Early response genes induced in chondrocytes stimulated with the inflammatory cytokine interleukin-1beta. Arthritis Res. 2001, 3: 381-388. 10.1186/ar331.Google Scholar

Dinarello CA: The IL-1 family and inflammatory diseases. Clin Exp Rheumatol. 2002, 20: S1-13.Google Scholar

Wolk K, Witte E, Hoffmann U, Doecke WD, et al: IL-22 induces lipopolysaccharide-binding protein in hepatocytes: A potential systemic role of IL-22 in Crohn's disease. J Immunol. 2007, 178: 5973-5981.Google Scholar

Hsu YH, Li HH, Hsieh MY, Liu MF, et al: Function of interleukin-20 as a proinflammatory molecule in rheumatoid and experimental arthritis. Arthritis Rheum. 2006, 54: 2722-2733. 10.1002/art.22039.Google Scholar

Ikeuchi H, Kuroiwa T, Hiramatsu N, Kaneko Y, et al: Expression of interleukin-22 in rheumatoid arthritis: Potential role as a proinflammatory cytokine. Arthritis Rheum. 2005, 52: 1037-1046. 10.1002/art.20965.Google Scholar

Otkjaer K, Kragballe K, Funding AT, Clausen JT, et al: The dynamics of gene expression of interleukin-19 and interleukin-20 and their receptors in psoriasis. Br J Dermatol. 2005, 153: 911-918. 10.1111/j.1365-2133.2005.06800.x.Google Scholar

Salvi GE, Lang NP: Host response modulation in the management of periodontal diseases. J Clin Periodontol. 2005, 32 (Suppl. 6): 108-129.Google Scholar

Burger D, Dayer JM, Palmer G, Gabay C: Is IL-1 a good therapeutic target in the treatment of arthritis?. Best Pract Res Clin Rheumatol. 2006, 20: 879-896. 10.1016/j.berh.2006.06.004.Google Scholar

Thornberry NA, Bull HG, Calaycay JR, Chapman KT, et al: A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes. Nature. 1992, 356: 768-774. 10.1038/356768a0.Google Scholar

Hayakawa M, Hayakawa H, Matsuyama Y, Tamemoto H, et al: Mature interleukin-33 is produced by calpain-mediated cleavage in vivo. Biochem Biophys Res Commun. 2009, 387: 218-222. 10.1016/j.bbrc.2009.07.018.Google Scholar

Talabot-Ayer D, Lamacchia C, Gabay C, Palmer G: Interleukin-33 is biologically active independently of caspase-1 cleavage. J Biol Chem. 2009, 284: 19420-19426. 10.1074/jbc.M901744200.Google Scholar

Thompson RC, Dripps DJ, Eisenberg SP: IL-1ra: Properties and uses of an interleukin-1 receptor antagonist. Agents Actions Suppl. 1991, 35: 41-49.Google Scholar

Kakkar R, Lee RT: The IL-33/ST2 pathway: Therapeutic target and novel biomarker. Nat Rev Drug Discov. 2008, 7: 827-840. 10.1038/nrd2660.Google Scholar

Dale M, Nicklin MJ: Interleukin-1 receptor cluster: Gene organization of IL1R2, IL1R1, IL1RL2 (IL-1Rrp2), IL1RL1 (T1/ST2), and IL18R1 (IL-1Rrp) on human chromosome 2q. Genomics. 1999, 57: 177-179. 10.1006/geno.1999.5767.Google Scholar

Taylor SL, Renshaw BR, Garka KE, Smith DE, et al: Genomic organization of the interleukin-1 locus. Genomics. 2002, 79: 726-733. 10.1006/geno.2002.6752.Google Scholar

O'Neill LA: Interleukin-1 signal transduction. Int J Clin Lab Res. 1995, 25: 169-177. 10.1007/BF02592694.Google Scholar

Steinkasserer A, Spurr NK, Cox S, Jeggo P, et al: The human IL-1 receptor antagonist gene (IL1RN) maps to chromosome 2q14-q21, in the region of the IL-1 alpha and IL-1 beta loci. Genomics. 1992, 13: 654-657. 10.1016/0888-7543(92)90137-H.Google Scholar

Gracie JA, Robertson SE, McInnes IB: Interleukin-18. J Leukoc Biol. 2003, 73: 213-224. 10.1189/jlb.0602313.Google Scholar

Park LS, Martin U, Garka K, Gliniak B, et al: Cloning of the murine thymic stromal lymphopoietin (TSLP) receptor: Formation of a functional heteromeric complex requires interleukin 7 receptor. J Exp Med. 2000, 192: 659-670. 10.1084/jem.192.5.659.Google Scholar

Rochman Y, Spolski R, Leonard WJ: New insights into the regulation of T cells by gamma(c) family cytokines. Nat Rev Immunol. 2009, 9: 480-490. 10.1038/nri2580.Google Scholar

Liu YJ, Soumelis V, Watanabe N, Ito T, et al: TSLP: An epithelial cell cytokine that regulates T cell differentiation by conditioning dendritic cell maturation. Annu Rev Immunol. 2007, 25: 193-219. 10.1146/annurev.immunol.25.022106.141718.Google Scholar

Chang HC, Sehra S, Goswami R, Yao W, et al: The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nat Immunol. 2010, 11: 527-534.Google Scholar

Alves NL, Arosa FA, van Lier RA: Common gamma chain cytokines: Dissidence in the details. Immunol Lett. 2007, 108: 113-120. 10.1016/j.imlet.2006.11.006.Google Scholar

Nelms K, Keegan AD, Zamorano J, Ryan JJ, et al: The IL-4 receptor: Signaling mechanisms and biologic functions. Annu Rev Immunol. 1999, 17: 701-738. 10.1146/annurev.immunol.17.1.701.Google Scholar

Obiri NI, Leland P, Murata T, Debinski W, et al: The IL-13 receptor structure differs on various cell types and may share more than one component with IL-4 receptor. J Immunol. 1997, 158: 756-764.Google Scholar

Chiba Y, Todoroki M, Misawa M: Activation of signal transducer and activator of transcription factor 1 by interleukins-13 and -4 in cultured human bronchial smooth muscle cells. J Smooth Muscle Res. 2009, 45: 279-288. 10.1540/jsmr.45.279.Google Scholar

Kitamura T, Sato N, Arai K, Miyajima A: Expression cloning of the human IL-3 receptor cDNA reveals a shared beta subunit for the human IL-3 and GM-CSF receptors. Cell. 1991, 66: 1165-1174. 10.1016/0092-8674(91)90039-2.Google Scholar

Takatsu K, Takaki S, Hitoshi Y: Interleukin-5 and its receptor system: Implications in the immune system and inflammation. Adv Immunol. 1994, 57: 145-190.Google Scholar

Gearing DP, King JA, Gough NM, Nicola NA: Expression cloning of a receptor for human granulocyte-macrophage colony-stimulating factor. EMBO J. 1989, 8: 3667-3676.Google Scholar

Yang LP, Byun DG, Demeure CE, Vezzio N, et al: Default development of cloned human naive CD4 T cells into interleukin-4-and interleukin-5-producing effector cells. Eur J Immunol. 1995, 25: 3517-3520. 10.1002/eji.1830251247.Google Scholar

Pacor S, Gagliardi R, Spessotto P, Zabucchi G, et al: Paracrine effects of IL-4 transfection on TS/A adenocarcinoma cells mediate reduced in vivo growth. Pathol Oncol Res. 1999, 5: 110-116. 10.1053/paor.1999.0172.Google Scholar

Holgate ST, Polosa R: Treatment strategies for allergy and asthma. Nat Rev Immunol. 2008, 8: 218-230. 10.1038/nri2262.Google Scholar

Jazayeri JA, Carroll GJ, Vernallis AB: Interleukin-6 subfamily cytokines and rheumatoid arthritis: Role of antagonists. Int Immunopharmacol. 2010, 10: 1-8. 10.1016/j.intimp.2009.09.019.Google Scholar

Heinrich PC, Behrmann I, Haan S, Hermanns HM, et al: Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J. 2003, 374: 1-20. 10.1042/BJ20030407.Google Scholar

Diveu C, Lak-Hal AH, Froger J, Ravon E, et al: Predominant expression of the long isoform of GP130-like (GPL) receptor is required for interleukin-31 signaling. Eur Cytokine Netw. 2004, 15: 291-302.Google Scholar

Ward LD, Hammacher A, Howlett GJ, Matthews JM, et al: Influence of interleukin-6 (IL-6) dimerization on formation of the high affinity hexameric IL-6. receptor complex. J Biol Chem. 1996, 271: 20138-20144. 10.1074/jbc.271.33.20138.Google Scholar

Hilton DJ, Hilton AA, Raicevic A, Rakar S, et al: Cloning of a murine IL-11 receptor alpha-chain: Requirement for gp130 for high affinity binding and signal transduction. EMBO J. 1994, 13: 4765-4775.Google Scholar

Plun-Favreau H, Perret D, Diveu C, Froger J, et al: Leukemia inhibitory factor (LIF), cardiotrophin-1, and oncostatin M share structural binding determinants in the immunoglobulin-like domain of LIF receptor. J Biol Chem. 2003, 278: 27169-27179. 10.1074/jbc.M303168200.Google Scholar

Silver JS, Hunter CA: gp130 at the nexus of inflammation, autoimmunity, and cancer. J Leukoc Biol. 2010,Google Scholar

Chattopadhyay S, Tracy E, Liang P, Robledo O, et al: Interleukin-31 and oncostatin-M mediate distinct signaling reactions and response patterns in lung epithelial cells. J Biol Chem. 2007, 282: 3014-3026.Google Scholar

Trinchieri G, Pflanz S, Kastelein RA: The IL-12 family of heterodimeric cytokines: New players in the regulation of T cell responses. Immunity. 2003, 19: 641-644. 10.1016/S1074-7613(03)00296-6.Google Scholar

Chua AO, Chizzonite R, Desai BB, Truitt TP, et al: Expression cloning of a human IL-12 receptor component. A new member of the cytokine receptor superfamily with strong homology to gp130. J Immunol. 1994, 153: 128-136.Google Scholar

Parham C, Chirica M, Timans J, Vaisberg E, et al: A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit IL-23R. J Immunol. 2002, 168: 5699-5708.Google Scholar

Larousserie F, Bardel E, Pflanz S, Arnulf B, et al: Analysis of interleukin-27 (EBI3/p28) expression in Epstein-Barr virus- and human T-cell leukemia virus type 1-associated lymphomas: Heterogeneous expression of EBI3 subunit by tumoral cells. Am J Pathol. 2005, 166: 1217-1228. 10.1016/S0002-9440(10)62340-1.Google Scholar

Pflanz S, Hibbert L, Mattson J, Rosales R, et al: WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27. J Immunol. 2004, 172: 2225-2231.Google Scholar

Brunda MJ: Interleukin-12. J Leukoc Biol. 1994, 55: 280-288.Google Scholar

Oppmann B, Lesley R, Blom B, Timans JC, et al: Novel pp19 protein engages IL-12p40 to form a cytokine IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000, 13: 715-725. 10.1016/S1074-7613(00)00070-4.Google Scholar

Niedbala W, Wei XQ, Cai B, Hueber AJ, et al: IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells. Eur J Immunol. 2007, 37: 3021-3029. 10.1002/eji.200737810.Google Scholar

Collison LW, Workman CJ, Kuo TT, Boyd K, et al: The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature. 2007, 450: 566-569. 10.1038/nature06306.Google Scholar

Hunter CA: New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions. Nat Rev Immunol. 2005, 5: 521-531. 10.1038/nri1648.Google Scholar

Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW: Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene. 2002, 285: 1-24. 10.1016/S0378-1119(02)00398-0.Google Scholar

Heinrich PC, Behrmann I, Muller-Newen G, Schaper F, et al: Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J. 1998, 334 (Pt. 2): 297-314.Google Scholar

Gadina M, Ferguson PR, Johnston JA: New interleukins: Are there any more?. Curr Opin Infect Dis. 2003, 16: 211-217. 10.1097/00001432-200306000-00005.Google Scholar

Goriely S, Cavoy R, Goldman M: Interleukin-12 family members and type I interferons in Th17-mediated inflammatory disorders. Allergy. 2009, 64: 702-709. 10.1111/j.1398-9995.2009.02039.x.Google Scholar

Fujihashi K, Kono Y, Kiyono H: Effects of IL6 on B cells in mucosal immune response and inflammation. Res Immunol. 1992, 143: 744-749. 10.1016/0923-2494(92)80015-D.Google Scholar

Van SJ, Renauld JC, Simpson RJ, Uyttenhove C, et al: Mouse Il-6. A hybridoma growth factor with multiple effects on normal B, T cells. Ann NY Acad Sci. 1989, 557: 206-13.Google Scholar

Schwertschlag US, Trepicchio WL, Dykstra KH, Keith JC, et al: Hematopoietic, immunomodulatory and epithelial effects of interleukin-11. Leukemia. 1999, 13: 1307-1315. 10.1038/sj.leu.2401514.Google Scholar

Collison LW, Vignali DA: Interleukin-35: Odd one out or part of the family?. Immunol Rev. 2008, 226: 248-262. 10.1111/j.1600-065X.2008.00704.x.Google Scholar

Castellani ML, Anogeianaki A, Felaco P, Toniato E, et al: IL-35. an anti-inflammatory cytokine which expands CD4+CD25+ Treg Cells. J Biol Regul Homeost Agents. 2010, 24: 131-135.Google Scholar

Monteleone G, Biancone L, Marasco R, Morrone G, et al: Interleukin 12 is expressed and actively released by Crohn's disease intestinal lamina propria mononuclear cells. Gastroenterology. 1997, 112: 1169-1178. 10.1016/S0016-5085(97)70128-8.Google Scholar

Zheng T, Zhu Z, Wang J, Homer RJ, et al: IL-11: Insights in asthma from overexpression transgenic modeling. J Allergy Clin Immunol. 2001, 108: 489-496. 10.1067/mai.2001.118510.Google Scholar

Fiorentino DF, Bond MW, Mosmann TR: Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med. 1989, 170: 2081-2095. 10.1084/jem.170.6.2081.Google Scholar

Zdanov A: Structural features of the interleukin-10 family of cytokines. Curr Pharm Des. 2004, 10: 3873-3884. 10.2174/1381612043382602.Google Scholar

Del PG, De CM, Almerigogna F, Giudizi MG, et al: Human IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cell clones and inhibits their antigen-specific proliferation and cytokine production. J Immunol. 1993, 150: 353-360.Google Scholar

Murray PJ: The JAK-STAT signaling pathway: Input and output integration. J Immunol. 2007, 178: 2623-2629.Google Scholar

Pletnev S, Magracheva E, Kozlov S, Tobin G, et al: Characterization of the recombinant extracellular domains of human interleukin-20 receptors and their complexes with interleukin-19 and interleukin-20. Biochemistry. 2003, 42: 12617-12624. 10.1021/bi0354583.Google Scholar

Liao YC, Liang WG, Chen FW, Hsu JH, et al: IL-19 induces production of IL-6 and TNF-alpha and results in cell apoptosis through TNF-alpha. J Immunol. 2002, 169: 4288-4297.Google Scholar

Liu L, Ding C, Zeng W, Heuer JG, et al: Selective enhancement of multipotential hematopoietic progenitors in vitro and in vivo by IL-20. Blood. 2003, 102: 3206-3209. 10.1182/blood-2003-05-1419.Google Scholar

Sabat R, Wallace E, Endesfelder S, Wolk K: IL-19 and IL-20: Two novel cytokines with importance in inflammatory diseases. Expert Opin Ther Targets. 2007, 11: 601-612. 10.1517/14728222.11.5.601.Google Scholar

Kingo K, Mossner R, Koks S, Ratsep R, et al: Association analysis of IL19, IL20 and IL24 genes in palmoplantar pustulosis. Br J Dermatol. 2007, 156: 646-652. 10.1111/j.1365-2133.2006.07731.x.Google Scholar

Kingo K, Mossner R, Ratsep R, Raud K, et al: Association analysis of IL20RA and IL20RB genes in psoriasis. Genes Immun. 2008, 9: 445-451. 10.1038/gene.2008.36.Google Scholar

Parrish-Novak J, Xu W, Brender T, Yao L, et al: Interleukins 19, 20, and 24 signal through two distinct receptor complexes. Differences in receptor-ligand interactions mediate unique biological functions. J Biol Chem. 2002, 277: 47517-47523. 10.1074/jbc.M205114200.Google Scholar

Xie MH, Aggarwal S, Ho WH, Foster J, et al: Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R. J Biol Chem. 2000, 275: 31335-31339.Google Scholar

Wolk K, Kunz S, Asadullah K, Sabat R: Cutting edge: Immune cells as sources and targets of the IL-10 family members?. J Immunol. 2002, 168: 5397-5402.Google Scholar

Liang SC, Tan XY, Luxenberg DP, Karim R, et al: Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med. 2006, 203: 2271-2279. 10.1084/jem.20061308.Google Scholar

Misse D, Yssel H, Trabattoni D, Oblet C, et al: IL-22 participates in an innate anti-HIV-1 host-resistance network through acute-phase protein induction. J Immunol. 2007, 178: 407-415.Google Scholar

de Oliveira NM, Ferreira JR, Colau D, Fischer H, et al: Interleukin-22 forms dimers that are recognized by two interleukin-22R1 receptor chains. Biophys J. 2008, 94: 1754-1765. 10.1529/biophysj.107.112664.Google Scholar

Chang C, Magracheva E, Kozlov S, Fong S, et al: Crystal structure of interleukin-19 defines a new subfamily of helical cytokines. J Biol Chem. 2003, 278: 3308-3313. 10.1074/jbc.M208602200.Google Scholar

Jiang H, Lin JJ, Su ZZ, Goldstein NI, et al: Subtraction hybridization identifies a novel melanoma differentiation associated gene, mda-7, modulated during human melanoma differentiation, growth and progression. Oncogene. 1995, 11: 2477-2486.Google Scholar

Commins S, Steinke JW, Borish L: The extended IL-10 superfamily: IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29. J Allergy Clin Immunol. 2008, 121: 1108-1111. 10.1016/j.jaci.2008.02.026.Google Scholar

Caudell EG, Mumm JB, Poindexter N, Ekmekcioglu S, et al: The protein product of the tumor suppressor gene, melanoma differentiation-associated gene 7, exhibits immunostimulatory activity and is designated IL-24. J Immunol. 2002, 168: 6041-6046.Google Scholar

Hor S, Pirzer H, Dumoutier L, Bauer F, et al: The T-cell lymphokine interleukin-26 targets epithelial cells through the interleukin-20 receptor 1 and interleukin-10 receptor 2 chains. J Biol Chem. 2004, 279: 33343-33351. 10.1074/jbc.M405000200.Google Scholar

Dambacher J, Beigel F, Zitzmann K, De Toni EN, et al: The role of the novel Th17 cytokine IL-26 in intestinal inflammation. Gut. 2009, 58: 1207-1217. 10.1136/gut.2007.130112.Google Scholar

Igawa D, Sakai M, Savan R: An unexpected discovery of two interferon gamma-like genes along with interleukin (IL)-22 and -26 from teleost: IL-22 and -26 genes have been described for the first time outside mammals. Mol Immunol. 2006, 43: 999-1009. 10.1016/j.molimm.2005.05.009.Google Scholar

Kotenko SV, Gallagher G, Baurin VV, Lewis-Antes A, et al: IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol. 2003, 4: 69-77.Google Scholar

Dellgren C, Gad HH, Hamming OJ, Melchjorsen J, et al: Human interferon-lambda3 is a potent member of the type III interferon family. Genes Immun. 2009, 10: 125-131. 10.1038/gene.2008.87.Google Scholar

Witte K, Gruetz G, Volk HD, Looman AC, et al: Despite IFN-lambda receptor expression, blood immune cells, but not keratino-cytes or melanocytes, have an impaired response to type III interferons: implications for therapeutic applications of these cytokines. Genes Immun. 2009, 10: 702-714. 10.1038/gene.2009.72.Google Scholar

Dumoutier L, Tounsi A, Michiels T, Sommereyns C, et al: Role of the interleukin (IL)-28 receptor tyrosine residues for antiviral and antiproliferative activity of IL-29/interferon-lambda 1: Similarities with type I interferon signaling. J Biol Chem. 2004, 279: 32269-32274. 10.1074/jbc.M404789200.Google Scholar

Coccia EM, Severa M, Giacomini E, Monneron D, et al: Viral infection and Toll-like receptor agonists induce a differential expression of type I and lambda interferons in human plasmacytoid and monocyte-derived dendritic cells. Eur J Immunol. 2004, 34: 796-805. 10.1002/eji.200324610.Google Scholar

Robek MD, Boyd BS, Chisari FV: Lambda interferon inhibits hepatitis B and C virus replication. J Virol. 2005, 79: 3851-3854. 10.1128/JVI.79.6.3851-3854.2005.Google Scholar

Ank N, Iversen MB, Bartholdy C, Staeheli P, et al: An important role for type III interferon (IFN-lambda/IL-28) in TLR-induced antiviral activity. J Immunol. 2008, 180: 2474-2485.Google Scholar

Lasfar A, Lewis-Antes A, Smirnov SV, Anantha S, et al: Characterization of the mouse IFN-lambda ligand-receptor system: IFN-lambdas exhibit antitumor activity against B16 melanoma. Cancer Res. 2006, 66: 4468-4477. 10.1158/0008-5472.CAN-05-3653.Google Scholar

Rouvier E, Luciani MF, Mattei MG, Denizot F, et al: CTLA-8, cloned from an activated T cell, bearing AU-rich messenger RNA instability sequences, and homologous to a herpesvirus saimiri gene. J Immunol. 1993, 150: 5445-5456.Google Scholar

Wright JF, Guo Y, Quazi A, Luxenberg DP, et al: Identification of an interleukin 17F/17A heterodimer in activated human CD4+ T cells. J Biol Chem. 2007, 282: 13447-13455. 10.1074/jbc.M700499200.Google Scholar

Chang SH, Dong C: A novel heterodimeric cytokine consisting of IL-17 and IL-17F regulates inflammatory responses. Cell Res. 2007, 17: 435-440.Google Scholar

Shi Y, Ullrich SJ, Zhang J, Connolly K, et al: A novel cytokine receptor-ligand pair. Identification, molecular characterization, and in vivo immunomodulatory activity. J Biol Chem. 2000, 275: 19167-19176. 10.1074/jbc.M910228199.Google Scholar

Gaffen SL: Structure and signalling in the IL-17 receptor family. Nat Rev Immunol. 2009, 9: 556-567. 10.1038/nri2586.Google Scholar

Korn T, Bettelli E, Oukka M, Kuchroo VK: IL-17 and Th17 Cells. Annu Rev Immunol. 2009, 27: 485-517. 10.1146/annurev.immunol.021908.132710.Google Scholar

Fort MM, Cheung J, Yen D, Li J, et al: IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity. 2001, 15: 985-995. 10.1016/S1074-7613(01)00243-6.Google Scholar

Ziolkowska M, Koc A, Luszczykiewicz G, Ksiezopolska-Pietrzak K, et al: High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporin A-sensitive mechanism. J Immunol. 2000, 164: 2832-2838.Google Scholar

Liu ZJ, Yadav PK, Su JL, Wang JS, et al: Potential role of Th17 cells in the pathogenesis of inflammatory bowel disease. World J Gastroenterol. 2009, 15: 5784-5788. 10.3748/wjg.15.5784.Google Scholar

Yu JJ, Gaffen SL: Interleukin-17: A novel inflammatory cytokine that bridges innate and adaptive immunity. Front Biosci. 2008, 13: 170-177. 10.2741/2667.Google Scholar

Shono T, Ono M, Izumi H, Jimi SI, et al: Involvement of the transcription factor NF-kappaB in tubular morphogenesis of human microvascular endothelial cells by oxidative stress. Mol Cell Biol. 1996, 16: 4231-4239.Google Scholar

Strieter RM, Kunkel SL, Showell HJ, Remick DG, et al: Endothelial cell gene expression of a neutrophil chemotactic factor by TNF-alpha LPS, and IL-1 beta. Science. 1989, 243: 1467-1469. 10.1126/science.2648570.Google Scholar

Yoshimura T, Matsushima K, Tanaka S, Robinson EA, et al: Purification of a human monocyte-derived neutrophil chemotactic factor that has peptide sequence similarity to other host defense cytokines. Proc Natl Acad Sci USA. 1987, 84: 9233-9237. 10.1073/pnas.84.24.9233.Google Scholar

Lakshminarayanan V, Drab-Weiss EA, Roebuck KA: H2O2 and tumor necrosis factor-alpha induce differential binding of the redox-responsive transcription factors AP-1 and NF-kappaB to the interleukin-8 promoter in endothelial and epithelial cells. J Biol Chem. 1998, 273: 32670-32678. 10.1074/jbc.273.49.32670.Google Scholar

Najakshin AM, Mechetina LV, Alabyev BY, Taranin AV: Identification of an IL-8 homolog in lamprey (Lampetra fluviatilis): Early evolutionary divergence of chemokines. Eur J Immunol. 1999, 29: 375-382. 10.1002/(SICI)1521-4141(199902)29:02<375::AID-IMMU375>3.0.CO;2-6.Google Scholar

Ambrus JL, Fauci AS: Human B lymphoma cell line producing B cell growth factor. J Clin Invest. 1985, 75: 732-739. 10.1172/JCI111754.Google Scholar

Ambrus JL, Chesky L, Stephany D, McFarland P, et al: Functional studies examining the subpopulation of human B lymphocytes responding to high molecular weight B cell growth factor. J Immunol. 1990, 145: 3949-3955.Google Scholar

Nogami S, Satoh S, Nakano M, Shimizu H, et al: Taxilin: A novel syntaxin-binding protein that is involved in Ca2+-dependent exocytosis in neuroendocrine cells. Genes Cells. 2003, 8: 17-28. 10.1046/j.1365-2443.2003.00612.x.Google Scholar

Nogami S, Satoh S, Tanaka-Nakadate S, Yoshida K, et al: Identification and characterization of taxilin isoforms. Biochem Biophys Res Commun. 2004, 319: 936-943. 10.1016/j.bbrc.2004.05.073.Google Scholar

Shen L, Suresh L, Li H, Zhang C, et al: IL-14 alpha, the nexus for primary Sjogren's disease in mice and humans. Clin Immunol. 2009, 130: 304-312. 10.1016/j.clim.2008.10.006.Google Scholar

Bacon K, Baggiolini M, Broxmeyer H, Horuk R, et al: Chemokine/chemokine receptor nomenclature. J Interferon Cytokine Res. 2002, 22: 1067-1068.Google Scholar

Zhang Y, Center DM, Wu DM, Cruikshank WW, et al: Processing and activation of pro-interleukin-16 by caspase-3. J Biol Chem. 1998, 273: 1144-1149. 10.1074/jbc.273.2.1144.Google Scholar

Baier M, Bannert N, Werner A, Lang K, et al: Molecular cloning, sequence, expression, and processing of the interleukin 16 precursor. Proc Natl Acad Sci USA. 1997, 94: 5273-5277. 10.1073/pnas.94.10.5273.Google Scholar

Wilson KC, Center DM, Cruikshank WW: The effect of interleukin-16 and its precursor on T lymphocyte activation and growth. Growth Factors. 2004, 22: 97-104. 10.1080/08977190410001704679.Google Scholar

Liu C, Mills J, Dixon K, Vennarini J, et al: IL-16 signaling specifically induces STAT6 activation through CD4. Cytokine. 2007, 38: 145-150. 10.1016/j.cyto.2007.05.016.Google Scholar

Cruikshank WW, Center DM, Nisar N, Wu M, et al: Molecular and functional analysis of a lymphocyte chemoattractant factor: Association of biologic function with CD4 expression. Proc Natl Acad Sci USA. 1994, 91: 5109-5113. 10.1073/pnas.91.11.5109.Google Scholar

Center DM, Kornfeld H, Cruikshank WW: Interleukin 16 and its function as a CD4 ligand. Immunol Today. 1996, 17: 476-481. 10.1016/0167-5699(96)10052-I.Google Scholar

Mathy NL, Scheuer W, Lanzendorfer M, Honold K, et al: Interleukin-16 stimulates the expression and production of pro-inflammatory cytokines by human monocytes. Immunology. 2000, 100: 63-69. 10.1046/j.1365-2567.2000.00997.x.Google Scholar

Glass WG, Sarisky RT, Vecchio AM: Not-so-sweet sixteen: The role of IL-16 in infectious and immune-mediated inflammatory diseases. J Interferon Cytokine Res. 2006, 26: 511-520. 10.1089/jir.2006.26.511.Google Scholar

Jemth P, Gianni S: PDZ domains: Folding and binding. Biochemistry. 2007, 46: 8701-8708. 10.1021/bi7008618.Google Scholar

Dahl CA, Schall RP, He HL, Cairns JS: Identification of a novel gene expressed in activated natural killer cells and T cells. J Immunol. 1992, 148: 597-603.Google Scholar

Kim SH, Han SY, Azam T, Yoon DY, et al: Interleukin-32: A cytokine and inducer of TNFalpha. Immunity. 2005, 22: 131-142.Google Scholar

Netea MG, Azam T, Ferwerda G, Girardin SE, et al: IL-32 synergizes with nucleotide oligomerization domain (NOD) 1 and NOD2 ligands for IL-1beta and IL-6 production through a caspase 1-dependent mechanism. Proc Natl Acad Sci USA. 2005, 102: 16309-16314. 10.1073/pnas.0508237102.Google Scholar

Conti P, Youinou P, Theoharides TC: Modulation of autoimmunity by the latest interleukins (with special emphasis on IL-32). Autoimmun Rev. 2007, 6: 131-137. 10.1016/j.autrev.2006.08.015.Google Scholar

Shioya M, Nishida A, Yagi Y, Ogawa A, et al: Epithelial overexpression of interleukin-32alpha in inflammatory bowel disease. Clin Exp Immunol. 2007, 149: 480-486. 10.1111/j.1365-2249.2007.03439.x.Google Scholar

Marcondes AM, Mhyre AJ, Stirewalt DL, Kim SH, et al: Dysregulation of IL-32 in myelodysplastic syndrome and chronic myelomonocytic leukemia modulates apoptosis and impairs NK function. Proc Natl Acad Sci USA. 2008, 105: 2865-2870. 10.1073/pnas.0712391105.Google Scholar

Rasool ST, Tang H, Wu J, Li W, et al: Increased level of IL-32 during human immunodeficiency virus infection suppresses HIV replication. Immunol Lett. 2008, 117: 161-167. 10.1016/j.imlet.2008.01.007.Google Scholar

Lin H, Lee E, Hestir K, Leo C, et al: Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science. 2008, 320: 807-811. 10.1126/science.1154370.Google Scholar

Wei S, Nandi S, Chitu V, Yeung YG, et al: Functional overlap but differential expression of CSF-1 and IL-34 in their CSF-1 receptor-mediated regulation of myeloid cells. J Leukoc Biol. 2010, 88: 495-505. 10.1189/jlb.1209822.Google Scholar

Garceau V, Smith J, Paton IR, Davey M, et al: Pivotal Advance: Avian colony-stimulating factor 1 (CSF-1), interleukin-34 (IL-34), and CSF-1 receptor genes and gene products. J Leukoc Biol. 2010, 87: 753-764. 10.1189/jlb.0909624.Google Scholar

Pandit J, Bohm A, Jancarik J, Halenbeck R, et al: Three-dimensional structure of dimeric human recombinant macrophage colony-stimulating factor. Science. 1992, 258: 1358-1362. 10.1126/science.1455231.Google Scholar