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-Guerin 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 (< 48 U/3 x 10(5) M-PHI/ml) by any M-PHI, whereas ligation of the Fc receptor for IgG1/IgG2(b) 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.