The enzymatic metabolism of membrane glycerophospholipids generates bioactive lysophospholipids including lysophosphatidic acid (LPA). LPA is present in normal serum, and is increased in concentration upon physiologic activation of platelets and other cell types. LPA has well-known growth effects on endothelium and lung structural cells, but its effects on other cell types are poorly understood. It was only recently appreciated that LPA exerts its cellular effects by binding a family of cell-surface molecules termed the endothelial differentiation gene, or Edg, receptors. The present study was prompted by our observations that: (i) Edg receptor mRNA is highly expressed in T lymphocytes and dendritic cells, (ii) LPA strikingly enhances the secretion of interleukin 13 (IL-13) from sub maximally activated T cells, and (iii) the concentration of LPA was enhanced in bronchoalveolar lavage fluids after segmental allergen challenge of human subjects. In ongoing research, we found that LPA influences dendritic cell maturation to inhibit IL-12 production, and that co-administration of LPA at the time of allergen sensitization in mice markedly augments lung eosinophilia in response to airway allergen challenge. We have developed a novel method to measure picomolar quantities of LPA and show that activated dendritic cells can release extracellular LPA. In a new collaboration, we have been provided access to a panel of high-titer antibodies directed against the three LPA receptors, and mice bearing targeted deletions in each of the LPA receptor genes Ipa1, Ipa2, and Ipa3. We propose four aims to dissect the role of LPA and its receptors in the allergic pulmonary immune response.
In Aim 1, we will define the molecular mechanisms by which LPA augments IL-13 expression in T cells, and test the hypothesis that this involves coupling of LPA receptors to MAPK and NF-kappaB activation.
In Aim 2, we will test the hypothesis LPA augments the differentiation of Th2 cells from naive CD4+ precursors under conditions of limiting antigen availability.
In Aim 3, we will use a mouse model of allergen sensitization and challenge and test the hypothesis that LPA and its receptors are required for T cell trafficking and pulmonary allergic inflammation.
In Aim 4, we will test the hypothesis that LPA primes lung dendritic cells for a Th2-promoting phenotype in vivo. Taken together, these studies will provide the first comprehensive analysis of a novel lysophospholipid and signal transduction pathway in allergic inflammatory diseases.
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