title: CD40-mediated activation of vascular smooth muscle cell chemokine production through a Src-initiated, MAPK-dependent pathway.
abstract: The interaction between CD40 ligand (CD154) expressed on activated T cells and its receptor, CD40, has been shown to play a role in the onset and maintenance of autoimmune inflammation. Recent studies suggest that CD154+T cells also contribute to the regulation of atherogenesis due to their capacity to activate CD40+cells of the vasculature, including vascular smooth muscle cells (VSMC). The present study evaluated the signalling events initiated through CD40 ligation which culminate in VSMC chemokine production. CD40 ligation resulted in the phosphorylation/activation of mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinases 1 and 2 (ERK1/2), and p38, but not c-jun N-terminal kinase. Inhibition of both ERK1/2 and p38 activity abrogated CD40 stimulation of IL-8 and MCP-1 production. CD40-mediated induction of chemokines also showed dependence on the Src family kinase activity. The Src kinase inhibitor, PP2, was found to inhibit CD40-induced phosphorylation of ERK1/2 as well as activation of IkappaB kinase. An evaluation of Src kinases that may be important in CD40 signalling identified Lyn as a potential candidate. These data indicate that CD40 signalling in VSMC activates a Src family kinase-initiated pathway that results in the induction of MAPK activities required for successful induction of chemokine synthesis.
authors.affiliation: Department of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY 40292, USA.
authors.forename: Lata
authors.initials: L
authors.lastname: Mukundan
authors.forename: Denise M
authors.initials: DM
authors.lastname: Milhorn
authors.forename: Bharati
authors.initials: B
authors.lastname: Matta
authors.forename: Jill
authors.initials: J
authors.lastname: Suttles
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism; D016466:CHO Cells; D018929:Cell Culture Techniques; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D018946:Chemokine CCL5 / Q000096:biosynthesis*; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation; D015870:Gene Expression; D016209:Interleukin-8 / Q000096:biosynthesis; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D019013:CD40 Antigens; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D016209:Interleukin-8; D023201:CD40 Ligand; D019061:src-Family Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases