Cytokine modulation of immune activation associated suppression of macrophage cyclooxygenase activity in vivo.
Intraperitoneal infection with Listeria monocytogenes (LM) results in activation of the peritoneal macrophage population which displays increased surface expression of major histocompatibility (MHC) Class II (Ia) antigen and markedly suppressed prostaglandin (PG) synthesis. We demonstrate here that this decrease in PG production is also seen after treatment by mitogen (Con A) and endotoxin (LPS), and can be explained by reduced cyclooxygenase activity in these cell populations. We show that, whereas Ia expression was augmented at all doses of LM and Con A tested, it displayed a biphasic response to LPS in vivo: increase at the lowest dose and inhibition at higher doses. In order to identify possible endogenous mediators of these responses, we used highly purified preparations of recombinant murine (rMu) cytokines and neutralizing cytokine specific monoclonal antibodies (MAbs) to examine whether interferon-gamma (IFN-gamma) and/or tumor necrosis factor (TNF) down-regulate macrophage cyclooxygenase activity in vivo. We found that IFN-gamma induced Ia expression but had no effect on PG secretion. In contrast, TNF-alpha suppressed PG synthesis and inhibited Ia surface expression. Similarly, in our model of Con A-induced peritoneal macrophage activation, pretreatment of animals with a neutralizing MAb to rMuIFN-gamma completely blocked the induction of Ia positive macrophages by Con A but did not affect Con A-dependent suppression of PG synthesis. Pretreatment with MAb to TNF had no effect on Con A-induced Ia levels, but significantly inhibited suppressed PG synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
Beckerman
K P
KP
Department of Pharmacology, Washington University School of Medicine, St Louis, MO 63110.
Schreiber
R D
RD
Needleman
P
P
D000818:Animals; D000911:Antibodies, Monoclonal; D003208:Concanavalin A / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology*; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008088:Listeriosis / Q000276:immunology; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D051379:Mice; D008808:Mice, Inbred CBA; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011453:Prostaglandins / Q000096:biosynthesis
D000911:Antibodies, Monoclonal; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D008070:Lipopolysaccharides; D011453:Prostaglandins; D003208:Concanavalin A; D011451:Prostaglandin-Endoperoxide Synthases