TARGETED SUPPRESSION OF CYTOKINE PRODUCTION IN MONOCYTES BUT NOT IN T-LYMPHOCYTES BY A TETRAVALENT GUANYLHYDRAZONE (CNI-1493)

Image analysis was used to study the cytokine-inhibitory effect of the nitric oxide inhibitor tetravalent guanylhydrazone (CNI-1493) in indi vidual immunocytochemically stained human peripheral blood mononuclear cells (PBMC), CNI-1493 inhibited lipopolysaccharide (LPS)-induced tum or necrosis factor (TNF)-alpha, interleukin (IL)-1 alpha, IL-1 beta, I L-6, and IL-8 production whether or not LPS stimulation was enhanced b y interferon (IFN)-gamma priming. Addition of TNF-alpha to CNI-1493-ex posed LPS-stimulated cells partially restored the incidence of IL-1 al pha-, IL-1 beta-, and IL-8-producing cells, TNF-alpha production induc ed by costimulation by ligation of CD3 and CD28 was inhibited by CNI-1 493 in monocytes but not in T lymphocytes, The prevalence of IL-2-, IF N-gamma-, and TNF-beta-producing T cells was not reduced by CNI-1493, Phorbol ester and ionomycin activation also resulted in a CNI-1493-ind uced inhibition of TNF-alpha in monocytes but resistant production of TNF-alpha, IL-2, and IFN-gamma by T cells, Thus, CNI-1493 preferential ly inhibited synthesis of proinflammatory cytokines in monocytes.