Inhibition of CD44, CD45 and LFA-3 mediated cytokine release from human monocytes by SK&F 86002 and pentoxifylline.
Compounds from two distinct pharmacological classes namely, SK&F 86002 and pentoxifylline, were examined for their effects on TNF alpha and IL-1 beta release by human monocytes stimulated with LPS or monoclonal antibodies to three cell surface glycoproteins, CD44, CD45 and LFA-3 (LFA-3 is also known as CD58). SK&F 86002, an inhibitor of 5-LO and CO in arachidonic acid metabolism, inhibited LPS-induced release of TNF alpha and IL-1 beta with an IC50 of 1 microM. At this dose, it also inhibited by > 50%, release of both cytokines induced by the three monoclonal antibodies. Pentoxifylline, a methylxanthine derivative with phosphodiesterase inhibitory activity, selectively inhibited LPS-induced TNF alpha release with an IC50 of 100 microM. TNF alpha and IL-1 beta release mediated by the monoclonal antibodies were inhibited by less than 30% in the presence of 100 microM pentoxifylline. These results suggest that (a) LPS induced cytokine release shares a common step with the physiologically relevant stimuli (involving cross-linking of cell surface receptors), and that this pathway is sensitive to inhibition by SK&F 86002 and, (b) SK&F 86002 is more potent than pentoxifylline in inhibiting TNF alpha and IL-1 beta release induced by both stimuli.
Prabhakar
U
U
Department of Cellular Biochemistry and Immunology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406.
Lipshutz
D
D
Truneh
A
A
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018968:CD58 Antigens; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000096:biosynthesis*; D017493:Leukocyte Common Antigens; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D010431:Pentoxifylline / Q000494:pharmacology; D016201:Receptors, Lymphocyte Homing; D013844:Thiazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018968:CD58 Antigens; D007093:Imidazoles; D007375:Interleukin-1; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016201:Receptors, Lymphocyte Homing; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; C052026:6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo(2,1-b)thiazole; D017493:Leukocyte Common Antigens; D010431:Pentoxifylline