Faculty Research 1990 - 1999

Title

CSF-1 (M-CSF) differentially sensitizes mononuclear phagocyte subpopulations to endotoxin in vivo: a potential pathway that regulates the severity of gram-negative infections.

Document Type

Article

Publication Date

1998

Keywords

Drug-Synergism, Gene-Expression: de, Gram-Negative-Bacterial-Infections: im, Interleukin-6: ge, Lipopolysaccharides: to, Macrophage-Colony-Stimulating-Factor, Macrophages: de, ph, Male, Mice, Mice-Inbred-C57BL, Monocytes: de, ph, RNA-Messenger: ge, SUPPORT-NON-U-S-GOVT, SUPPORT-U-S-GOVT-P-H-S, Time-Factors, Tumor-Necrosis-Factor: ge

JAX Source

J Leukoc Biol 1998 Feb;63(2):245-52

Grant

CA27523/CA/NCI

Abstract

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). Indeed, when CSF-1-primed mice were challenged with lipopolysaccharide (LPS), increased levels of serum IL-6 and TNF-alpha were detected. Both intravenous and intraperitoneal injections of CSF-1 resulted in increased sensitivity to LPS challenge, which induced maximum increases in serum IL-6 when administered via the intraperitoneal route. The peak serum IL-6 production in control and CSF-1-primed mice occurred 2-3 h after LPS injection, whereas that of TNF-alpha occurred by 1-2 h. When peripheral blood leukocytes, spleen cells, and resident peritoneal cells (PC) were isolated from CSF-1-primed mice injected with LPS, only the PC were shown to release IL-6 constitutively and none released TNF-alpha. A comparison of mRNA isolated from various cells and tissues after intraperitoneal CSF-1 priming indicated that only PC expressed IL-6 mRNA, whereas PC, liver, and spleen expressed TNF-alpha mRNA. All tissues 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, lung, and kidney showed enhanced TNF-alpha expression. These data indicate 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 CSF-1 plays an important role in regulating the sensitivity of the host to the pathophysiological effects of endotoxin.

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