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IL-4 Regulates MEK Expression Required for Lysophosphatidic Acid-Mediated Chemokine Generation by Human Mast Cells¹

Debby A. Lin^* and Joshua A. Boyce^2,*,

^* Departments of Medicine and Pediatrics, Harvard Medical School, and Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Boston, MA 02115; and Partners Asthma Center, Boston, MA 02115

IL-4 and mast cells (MCs) mediate mucosal defense against helminths and are central to allergic inflammation. Lysophosphatidic acid (LPA), an abundant, potent lipid growth factor, stimulates the growth of cultured human MCs (hMCs) in vitro through a pathway involving LPA receptors 1 and 3 (termed the LPA₁ and LPA₃ receptors, respectively) and peroxisome proliferator-activated receptor-. We now report that LPA potently induces the generation of proinflammatory chemokines (MIP-1, IL-8, and MCP-1) by hMCs by a mechanism that absolutely requires IL-4. The de novo expression of chemokine mRNA and protein generation involves synergistic actions of calcium flux-dependent NFAT transcription factors and ERK. ERK phosphorylation and chemokine production in response to LPA require IL-4-dependent up-regulation of MEK-1 expression by a pathway involving PI3K. Although receptor-selective agonists for both the LPA₂ and LPA₃ receptors induce calcium fluxes by hMCs, only the LPA₂ receptor-selective agonist fatty alcohol phosphate-12 mimics the IL-4-dependent effect of LPA on chemokine generation. The fact that LPA, an endogenous lipid mediator, activates hMCs by an LPA₂ receptor-dependent pathway indicates functional distinctions between different LPA receptor family members that are expressed constitutively by cells of a single hemopoietic lineage. Moreover, the regulation of MEK-dependent signaling is a mechanism by which IL-4 could amplify inflammation in mucosal immune responses through receptor systems for endogenous ligands such as LPA.

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