Regulation of tumor necrosis factor (TNF) release by murine peritoneal macrophages: role of cell stimulation and specific phagocytic plasma membrane receptors

In spite of the physiologic and pathologic importance of tumor necrosis factor (TNF), the cellular factors that govern its release by macrophages (M phi) are poorly understood, in comparison with other secretory products. We have studied the role of M phi heterogeneity and of plasma membrane receptors in regulating TNF release in vitro. Resident and various exudate murine peritoneal M phi populations were challenged with lipopolysaccharide (LPS) or different phagocytic particles, and TNF release assayed by cytotoxicity for L-929 fibroblasts. Resident peritoneal M phi (RPM phi) released a small amount of TNF in response to LPS whereas thioglycollate-elicited M phi (TPM phi) released high levels of TNF (5000 U/3 x 10(5) M phi/ml). M phi elicited by Bio-Gel polyacrylamide beads (BgPM phi), another nonspecific inflammatory stimulus, or early in the course of intraperitoneal Bacillus Calmette-Guérin infection, before recruited cells become immunologically activated, released tenfold less TNF after the same stimulus. By contrast, TNF release in response to various phagocytic triggers was similar (approximately 300-600 U/3 x 10(5) M phi/ml) in all M phi populations including RPM phi. The response by BgPM phi to LPS was enhanced by pre-treatment in vitro with interferon-gamma or thioglycollate broth. With respect to phagocytic receptor triggering we found that complement receptor type 3 (CR3) ligation or latex uptake did not mediate release of significant quantities of TNF (less than 48 U/3 x 10(5) M phi/ml) by any M phi, whereas ligation of the Fc receptor for IgG1/IgG2b subclasses or of receptors for zymosan particles sufficed, in the absence of ingestion, to induce release of circa 500 U/3 x 10(5) M phi/ml TNF by all M phi tested. Our studies show that M phi vary in respect to priming for TNF release and that heterogeneity should be related to a particular triggering stimulus. Furthermore, the capacity of some M phi populations to release unusually high levels of TNF depends on immune or nonspecific stimuli subsequent to the process of inflammatory recruitment.