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 individual immunocytochemically stained human peripheral blood mononuclear cells (PBMC). CNI-1493 inhibited lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-alpha, interleukin (IL)-1alpha, IL-1beta, IL-6, and IL-8 production whether or not LPS stimulation was enhanced by interferon (IFN)-gamma priming. Addition of TNF-alpha to CNI-1493-exposed LPS-stimulated cells partially restored the incidence of IL-1alpha-, IL-1beta-, and IL-8-producing cells. TNF-alpha production induced by costimulation by ligation of CD3 and CD28 was inhibited by CNI-1493 in monocytes but not in T lymphocytes. The prevalence of IL-2-, IFN-gamma-, and TNF-beta-producing T cells was not reduced by CNI-1493. Phorbol ester and ionomycin activation also resulted in a CNI-1493 -induced inhibition of TNF-alpha in monocytes but resistant production of TNF-alpha, IL-2, and IFN-gamma by T cells. Thus, CNI-1493 preferentially inhibited synthesis of proinflammatory cytokines in monocytes.
Björk
L
L
Department of Immunology, WennerGren Institute, Stockholm University, Sweden.
Tracey
K J
KJ
Ulrich
P
P
Bianchi
M
M
Cohen
P S
PS
Akerlund
K
K
Fehniger
T E
TE
Andersson
U
U
Andersson
J
J
D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007375:Interleukin-1 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000813:Anilides; D006146:Guanidines
D016207:Cytokines; D006835:Hydrazones; D007166:Immunosuppressive Agents; D007375:Interleukin-1; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; C097256:semapimod; D000813:Anilides; D006146:Guanidines