CSF-1 (M-CSF) DIFFERENTIALLY SENSITIZES MONONUCLEAR PHAGOCYTE SUBPOPULATIONS TO ENDOTOXIN IN-VIVO - A POTENTIAL PATHWAY THAT REGULATES THE SEVERITY OF GRAM-NEGATIVE INFECTIONS

CSF-1 is known to prime mononuclear phagocytes (MNP) for inflammatory stimuli in vitro. We hypothesized that CSF-1 in vivo can sensitize the host to the increased production of endotoxic shock mediators such as tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6). Ind eed, when CSF-1-primed mice were challenged with lipopolysaccharide (L PS), increased levels of serum IL-6 and TNF-alpha were detected. Both intravenous and intraperitoneal injections of CSF-1 resulted in increa sed sensitivity to LPS challenge, which induced maximum increases in s erum IL-6 when administered via the intraperitoneal route. The peak se rum IL-6 production in control and CSF-1-primed mice occurred 2-3 h af ter LPS injection, whereas that of TNF-alpha occurred by 1-2 h. When p eripheral blood leukocytes, spleen cells, and resident peritoneal cell s (PC) were isolated from CSF-1-primed mice injected with LPS, only th e PC were shown to release IL-6 constitutively and none released TNF-a lpha. A comparison of mRNA isolated from various cells and tissues aft er intraperitoneal CSF-1 priming indicated that only PC expressed IL-6 mRNA, whereas PC, liver, and spleen expressed TNF-alpha mRNA. All tis sues showed increased levels of IL-6 and TNF-alpha mRNA in response to LPS challenge. Only liver and kidney showed an enhanced level of IL-6 expression in CSF-1-primed mice challenged with LPS, whereas liver, l ung, and kidney showed enhanced TNF-alpha expression. These data indic ate that CSF-1 primes tissue MNP but not circulating MNP to transcribe mRNA and release IL-6 and TNF-alpha. Overall, the data suggest that C SF-1 plays an important role in regulating the sensitivity of the host to the pathophysiological effects of endotoxin.