Lipids have diverse and complex cellular functions, acting as membrane phospholipid constituents, metabolic substrates, precursors for signaling molecules, and mediators of gene expression. Highly complex molecular pathways are required to regulate these activities and maintain intra- and extracellular lipid homeostasis. FABPs are considered to play a critical role in lipid homeostasis, although their precise molecular mode(s) of action are incompletely understood. The adipocyte FABP, aP2, has long been utilized as a specific adipocyte marker and has recently also been identified in macrophages (39
). aP2 is thought to regulate fatty acid uptake, release, and storage in adipocytes and participates in systemic glucose homeostasis and in macrophage responses in atherosclerosis (20
). Our findings now identify aP2 as an IL-4/IL-13–regulated gene in bronchial epithelial cells and demonstrate a key role for this FABP in Th2 cytokine-mediated airway inflammation.
The factors regulating aP2
expression have been widely studied in adipocytes, particularly during adipocyte differentiation. In adipocytes, aP2
expression is controlled predominantly by fatty acids and particularly by PPARγ agonists (41
). Despite the fact that they have a functional PPARγ signaling pathway, we found no evidence for PPARγ-mediated regulation of aP2
expression in HBEs. In airway epithelium, STAT6 was shown to be largely responsible for upregulation of aP2
by IL-4. The other major stimulus regulating aP2
expression in HBEs was the type 1 cytokine IFN-γ, which induced a significant downregulation. Upregulation by Th2 cytokines and downregulation by Th1 cytokines provided a strong indication that aP2 was involved in Th2 inflammation. This was further supported by the observation of increased aP2 expression in AECs of mice undergoing allergic airway inflammation.
The bronchial epithelium plays an active role in the asthmatic inflammatory response. In particular, STAT6-dependent responses to IL-4 and IL-13 in epithelial cells are thought to make a major contribution to disease pathogenesis (9
). A number of IL-4/IL-13–responsive, STAT6-dependent genes have been identified in airway epithelium, but in few cases has their contribution to allergic airway inflammation and cellular site of action been defined. The present study clearly identifies aP2 as a STAT6-dependent regulator of allergic airway inflammation, and we have made considerable effort to test whether AECs were the site of aP2 activity. Since aP2 is known to regulate inflammatory responses in macrophages (20
) and DCs (Rolph et al., manuscript submitted for publication), our studies focused on the potential contribution of these cell types. Using bone marrow chimeras and analyzing T cell responses in OVA-primed mice, we found no evidence for a contribution of aP2 in hematopoietic cells in allergic airway inflammation. In addition, allergic responses outside of the lung (in the peritoneal cavity) were unimpaired in aP2–/–
mice. Taken together with our in vitro and in vivo airway epithelial expression data, our data strongly suggests that the airway epithelium is the major site of action of aP2 in allergic airway inflammation.
aP2 has been widely studied in adipocytes, where it is thought to facilitate lipid transport and metabolism. In contrast, the role of aP2, and other FABPs, in inflammatory responses has received little attention. Understanding the molecular mechanism by which aP2 regulates allergic airway inflammation is likely to identify new signaling events that regulate inflammatory responses. aP2 has recently been described as a regulator of PPARγ and NF-κB in macrophages (44
). Both these transcription factors are present in, and regulate inflammatory responses of, AECs. However, a number of other plausible mechanisms are suggested by the ability of aP2 to bind a range of long-chain fatty acids. For example, aP2 binds arachidonic acid and a number of its metabolites (46
) and could modulate production or metabolism of bioactive eicosanoids. Indeed, recent studies have demonstrated that aP2 can bind the 5-lipoxygenase (5-LO) product leukotriene A4
(LTA4) and markedly extend its half-life (47
). 5-LO participates in a broad range of inflammatory diseases, but it appears to have a particularly strong involvement in asthma and atherosclerosis (48
). Our data, together with those of Makowski et al. (20
), now identify aP2 as an additional pathophysiological link between these 2 diseases. Since aP2 binds and stabilizes the 5-LO product LTA4, this suggests the intriguing possibility of a common pathway in asthma and atherosclerosis involving cooperation between aP2 and 5-LO in eicosanoid biosynthetic pathways, either by direct intracellular interaction or by transcellular biosynthesis (51
The identification of a FABP that regulates allergic airway inflammation emphasizes the importance of lipids in the inflammatory response, and our findings contribute to the emerging theme of overlap between inflammatory and metabolic pathways (39
). aP2 is a member of a larger family of FABPs with distinct patterns of tissue distribution (23
). The ability of aP2 to regulate inflammation may thus represent a general feature of FABP biology, implying a role for FABPs in a broad range of inflammatory diseases. Finally, our findings suggest blocking aP2 function as a novel approach for treatment of asthma and other inflammatory lung diseases.