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

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Abstract
In spite of the physiologic and pathologic importance of tumor necrosis factor (TNF), the cellular factors that govern its release by macrophages (MΦ) are poorly understood, in comparison with other secretory products. We have studied the role of MΦ heterogeneity and of plasma membrane receptors in regulating TNF release in vitro. Resident and various exudate murine peritoneal MΦ populations were challenged with lipopolysaccharide (LPS) or different phagocytic particles, and TNF release assayed by cytotoxicity for L‐929 fibroblasts. Resident peritoneal MΦ (RPMΦ) released a small amount of TNF in response to LPS whereas thioglycollate‐elicited MΦ (TPMΦ) released high levels of TNF (5000 U/3 × 105 MΦ/ml). MΦ elicited by Bio‐Gel polyacrylamide beads (BgPMΦ), 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 (∼300‐600 U/3 × 105 MΦ/ml) in all MΦ populations including RPMΦ. The response by BgPMΦ to LPS was enhanced by pre‐treatment in vitro with interferon‐γ 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 (5 MΦ/ml) by any MΦ, 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 × 105 MΦ/ml TNF by all MΦ tested. Our studies show that MΦ vary in respect to priming for TNF release and that heterogeneity should be related to a particular triggering stimulus. Furthermore, the capacity of some MΦ populations to release unusually high levels of TNF depends on immune or nonspecific stimuli subsequent to the process of inflammatory recruitment.

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