Mechanisms of tumor necrosis factor-alpha alteration of PMN adhesion and migration.
We have investigated the effects of recombinant human tumor necrosis factor-alpha (rhTNF alpha) on polymorphonuclear leukocytes (PMNs), concentrating on the mechanisms involved in the alterations of PMN-directed migration and adherence by this cytokine. RhTNF alpha profoundly suppressed PMN chemotaxis toward FMLP by 80%. At similar concentrations, it enhanced adhesion to gelatin-coated plastic dishes by more than tenfold and increased the expression of the CD11b antigen to 182% of the control. The monoclonal antibody 60.1, which is directed against the alpha chain of the CD11b/CD18 complex, completely blocked rhTNF alpha, induced inhibition of the chemotactic response to FMLP, and rhTNF alpha induced hyperadherence, suggesting that these effects were related to rhTNF alpha's effects on CD11b antigen expression. The fluid state of the PMN membrane was also decreased by rhTNF alpha. N-butanol, a known membrane fluidizer, partially inhibited the effect of rhTNF alpha on membrane fluidity and chemotaxis and completely reversed its effects on adherence and the expression of the CD11b antigen. Pentoxifylline, an agent that has previously been studied for its ability to prevent some effects of rhTNF alpha on PMNs, completely prevented the effect of rhTNF alpha on chemotaxis, the expression of the CD11b antigen, and membrane fluidity. Pentoxifylline partially prevented changes in adherence caused by this cytokine. Increased CD11b antigen expression caused by rhTNF alpha may result in enhanced PMN adhesion and suppression of migration. These events may, in turn, lead to the accumulation of PMNs on the vascular endothelium, resulting in the extensive vascular and tissue damage that is seen in gram-negative sepsis.
Salyer
J L
JL
Department of Pathology, University of Utah, Salt Lake City 84132.
Bohnsack
J F
JF
Knape
W A
WA
Shigeoka
A O
AO
Ashwood
E R
ER
Hill
H R
HR
D020001:1-Butanol; D000328:Adult; D015703:Antigens, CD / Q000032:analysis; D000943:Antigens, Differentiation / Q000032:analysis; D000440:Butanols / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D016177:Macrophage-1 Antigen; D008560:Membrane Fluidity / Q000187:drug effects; D009504:Neutrophils / Q000166:cytology*; D010431:Pentoxifylline / Q000494:pharmacology; D016028:Receptors, Leukocyte-Adhesion / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D000440:Butanols; D016177:Macrophage-1 Antigen; D016028:Receptors, Leukocyte-Adhesion; D014409:Tumor Necrosis Factor-alpha; D020001:1-Butanol; D010431:Pentoxifylline