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Activation of Macrophage CD8: Pharmacological Studies of TNF and IL-1ß Production¹

Tong-Jun Lin^2,*, Nadir Hirji^2,, Grant R. Stenton^2,, Mark Gilchrist, Brock J. Grill, Alan D. Schreiber and A. Dean Befus^3,

^* Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada; Pulmonary Research Group, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; and University of Pennsylvania School of Medicine, Philadelphia, PA, 19104

Previously, we demonstrated that rat macrophages express CD8 and that Ab to CD8 stimulates NO production. We confirm that CD8 is expressed by rat macrophages and extend understanding of its functional significance. Activation of CD8 (OX8 Ab) on alveolar macrophages stimulated mRNA expression for TNF and IL-1ß and promoted TNF and IL-1ß secretion. Similarly, OX8 Ab (CD8) stimulated NR8383 cells to secrete TNF, IL-1ß, and NO. Activation of CD8ß (Ab 341) on alveolar macrophages increased mRNA expression for TNF and IL-1ß and stimulated secretion of TNF, but not IL-1ß. Interestingly, anti-CD8 Abs did not stimulate IFN- or PGE₂ production, or phagocytosis by macrophages. OX8 (CD8)-induced TNF and IL-1ß production by macrophages was blocked by inhibitors of protein tyrosine kinase(s), PP1, and genistein, but not by phosphatidylinositol-3 kinase inhibitor, wortmannin. Moreover, OX8 stimulated protein tyrosine kinase activity in NR8383 cells. Further analysis of kinase dependence using antisense to Syk kinase demonstrated that TNF, but not IL-1ß, stimulation by CD8 is Syk dependent. By contrast, protein kinase C inhibitor Ro 31-8220 had no effect on OX8-induced TNF production, whereas OX8-induced IL-1ß production was blocked by Ro 31-8220. Thus, there are distinct signaling mechanisms involved in CD8 (OX8)-induced TNF and IL-1ß production. In summary, macrophages express CD8 molecules that, when activated, stimulate TNF and IL-1ß expression, probably through mechanisms that include activation of Src and Syk kinases and protein kinase C. These findings identify a previously unknown pathway of macrophage activation likely to be involved in host defense and inflammation.