REGULATION OF VCAM-1 EXPRESSION BY INTERLEUKIN 4

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Infiltration of inflammatory cells appears responsible for many of the pathologic changes that occur in the asthmatic airway. Adhesion of circulating inflammatory cells to the endothelium is the first step in recruitment of these cells to the lung. Vascular cell adhesion molecule-1 (VCAM-1) appears on the lung endothelium in asthmatics and recruits circulating eosinophils and lymphocytes through its interaction with alpha4beta1 and alpha4beta7 integrins on the surface of these cells. One of the cytokines that has been shown to be increased in the asthmatic airway is IL-4. There is some evidence that IL-4 is genetically linked to allergic asthma, and knocking out the IL-4 gene in mice or addition of anti-IL-4 antibody prevents a significant inflammatory response to allergen challenge in the lung, suggesting that this cytokine is critical for an efficient allergic inflammatory response. Other cytokines such as tumor necrosis factor-alpha (TNF) and IL-1 are also increased in asthmatics. We have found that these cytokines along with IL-4 play an important role in selectively and synergistically inducing expression of VCAM-1 on human pulmonary microvascular endothelial cells. TNF and IL-1 cause transcriptional activation of the VCAM-1 gene through kappaB sites in the promoter, whereas IL-4 stabilizes the resulting messages leading to both a synergistic increase in VCAM-1 expression and the prolonged appearance of VCAM-1 on the endothelial surface. Taken together, these results suggest that IL-4 plays an important role in selectively increasing VCAM-1 expression leading to recruitment of eosinophils and lymphocytes to the lung. We have found that IL-4 increases VCAM-1 mRNA stability through a novel mechanism that does not involve the traditional JAK/STAT pathway of IL-4 signal transduction. Therefore, we propose studies to examine this novel signaling pathway and to define molecular events leading to the stabilization of VCAM-1 mRNA. This will involve two complementary approaches: l) an "inside-out" approach to identify an IL-4 responsive cytoplasmic protein(s) that regulates VCAM-l mRNA stability, and to use this protein to discover cytoplasmic interactions leading back to the IL-4 receptor; 2) an "outside-in" approach beginning with the IL-4 receptor and leading to the IL-4 responsive cytoplasmic target protein that regulates VCAM-1 mRNA stability. To provide evidence of the functional link between IL-4 and VCAM-1 expression and recruitment of inflammatory cells in vivo, we will correlate expression of VCAM-1 with the infiltration of inflammatory cells into the mouse lung in response to allergen challenge in both wild-type and IL-4 gene knockout mice. As mentioned above, expression of VCAM-l, IL-I, TNF, and IL-4 have been shown to be increased in asthmatics. We propose to extend these studies by correlating the expression of VCAM-1, IL-4, and TNF both spatially and temporally with the recruitment of eosinophils and lymphocytes to the airway of human subjects in response to segmental allergen-challenge and withdrawal of inhaled glucocorticoid therapy. These studies will include allergic and intrinsic asthmatics. An eosinophil infiltrate is characteristic of both conditions. Although there is evidence of a role for IL-4 and VCAM-1 in inflammatory cell recruitment in allergic asthma, evidence for a corresponding role in intrinsic asthma still needs to be defined.