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Mechanisms of tumor necrosis factor-alpha alteration of PMN adhesion and migration
J L Salyer1, J F Bohnsack, W A Knape
1Department of Pathology, University of Utah, Salt Lake City 84132.
Abstract:
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.
Insights
Recombinant human tumor necrosis factor-alpha (rhTNF alpha) significantly impairs polymorphonuclear leukocyte (PMN) migration and increases adherence by affecting CD11b antigen expression. These changes may contribute to tissue damage in sepsis.
Area of Science:
- Immunology
- Cell Biology
- Pathophysiology
Background:
- Tumor necrosis factor-alpha (TNF alpha) is a key cytokine in inflammatory responses.
- Polymorphonuclear leukocytes (PMNs) play a critical role in host defense and inflammation.
- Dysregulated PMN function contributes to tissue damage in conditions like sepsis.
Purpose of the Study:
- To investigate the effects of recombinant human TNF alpha (rhTNF alpha) on PMN migration and adherence.
- To elucidate the mechanisms underlying rhTNF alpha-induced alterations in PMN function.
- To explore the role of CD11b antigen expression and membrane fluidity in these processes.
Main Methods:
- Assessing PMN chemotaxis towards FMLP.
- Measuring PMN adherence to gelatin-coated surfaces.
- Quantifying CD11b antigen expression on PMNs.
- Evaluating PMN membrane fluidity.
- Utilizing monoclonal antibody 60.1, N-butanol, and pentoxifylline as experimental modulators.
Main Results:
- rhTNF alpha suppressed PMN chemotaxis by 80% and enhanced adherence tenfold.
- rhTNF alpha increased CD11b antigen expression to 182% of control.
- Monoclonal antibody 60.1 blocked rhTNF alpha's effects on chemotaxis and adherence.
- N-butanol and pentoxifylline partially or completely reversed rhTNF alpha-induced changes.
- rhTNF alpha decreased PMN membrane fluidity.
Conclusions:
- rhTNF alpha-induced increase in CD11b expression enhances PMN adherence and suppresses migration.
- These functional alterations in PMNs may lead to vascular endothelium accumulation and tissue damage in sepsis.
- Pentoxifylline demonstrates potential in mitigating rhTNF alpha-mediated PMN dysfunction.