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The adipocyte fatty acid-binding protein aP2 regulates systemic glucose and lipid metabolism. We report that aP2, in addition to being abundantly expressed by adipocytes, is also expressed by human airway epithelial cells and shows a striking upregularion following stimulation of epithelial cells with the Th2 cytokines IL-4 and IL-13. Regulation of aP2 mRNA expression by Th2 cytokines was highly dependent on STAT6, a transcription factor with a major regulatory role in allergic inflammation. We examined aP2-deficient mice in a model of allergic airway inflammation and found that infiltration of leukocytes, especially eosinophils, into the airways was highly dependent on aP2 function. T cell priming was unaffected by aP2 deficiency, suggesting that aP2 was acting locally within the lung, and analysis of bone marrow chimeras implicated non-hematopoietic cells, most likely bronchial epithelial cells, as the site of action of aP2 in allergic airway inflammation. Thus, aP2 regulates allergic airway inflammation and may provide a link between fatty acid metabolism and asthma.
Nonstandard abbreviations used: AEC, airway epithelial cell; BAL, bronchoalveolar lavage; FABP, fatty acid-binding protein; HBE, human bronchial epithelial cell; 5-LO, 5-lipoxygenase; MCP-1, monocyte chemoattractant protein-1.
Introduction
Asthma is a chronic inflammatory disease characterized by airway hyperresponsiveness, tissue remodeling, and airflow obstruction (1). The underlying pathogenetic mechanisms in asthma are only partly understood, a situation reflected in the variable and incomplete responses by patients to current therapeutics. The incidence of asthma in Western countries has increased markedly over the last 20 years, and in countries such as the USA and Australia, it now affects approximately 10% of the population (2,3). Environmental factors must be largely responsible for this sudden increase in incidence. Current thinking is dominated by the hygiene hypothesis, according to which childhood microbial infection is a major determinant of predisposition to atopic asthma (4). Numerous additional environmental factors, such as diet, airborne pollution, and composition of gut commensal microflora are likely involved (S), and further hypotheses that account for the dramatic increase in asthma incidence are required.
Most cases of asthma are associated with characteristic airway immunopathology involving Th2 lymphocytes, eosinophils, mast cells, and goblet cell hyperplasia. The Th2 cytokines IL-4, IL-5, IL-9, and IL-13 initiate and promote asthma pathogenesis (1). IL-4 drives Th2 lymphocyte polarization and also induces IgE class switching. Its...