INTERACTION OF TUMOR-NECROSIS-FACTOR-ALPHA AND GRANULOCYTE-COLONY-STIMULATING FACTOR ON NEUTROPHIL APOPTOSIS, RECEPTOR EXPRESSION, AND BACTERICIDAL FUNCTION

Infected patients are likely to have increased levels of tumor necrosi s factor-alpha (TNF-alpha) and may be treated with recombinant human g ranulocyte colony-stimulating factor (G-CSF). Recombinant human TNF-al pha activates polymorphonuclear neutrophil (PMN) inflammatory activity . We examined the effect of exposure to TNF-alpha and G-CSF alone and in combination on PMN apoptosis, receptor expression, phagocytosis, an d bactericidal function. The results were compared to those obtained w ith a promoter of PMN apoptosis, cycloheximide. After 24 hr, 27% of PM Ns were nonapoptotic, and TNF-alpha (1 unit/ml) showed no change. Cycl oheximide (10 mu g/ml) decreased the number of nonapoptotic cells to 1 0% of the initial PMN. In contrast, G-CSF (30 ng/ml) decreased apoptos is (57% nonapoptotic PMN after 24 hr). Both G-CSF and TNF-alpha (but n ot cycloheximide) induced preservation of PMN Fc gamma RIII (467% and 167% of 24-hr controls, respectively) and beta(2)-integrin expression (150% and 168% of 24-hr controls, respectively). G-CSF (but not TNF-al pha or cycloheximide) stimulated expression of Fc gamma RI (191% of 24 -hr control) and Fc gamma RII (267% of 24-hr control). G-CSF (but not TNF-alpha) maintained the ability of PMN to ingest and kill opsonized Staphylococcus aureus. TNF-alpha decreased the effect of G-CSF on apop tosis, expression of Fc gamma RIII and Fc gamma RI, and bactericidal f unction. Thus, TNF-alpha promoted expression of Fc gamma RII and beta( 2)-integrin receptors, which are important for phagocytic activity, an d G-CSF diminished apoptosis, increased Fc gamma receptor expression, and maintained bactericidal function. TNF-alpha counteracted some effe cts of G-CSF. Interactions of these cytokines in vivo serve to regulat e the PMN inflammatory response and bactericidal capacity.