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*
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.
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