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CSF-1 (M-CSF) differentially sensitizes mononuclear phagocyte subpopulations to endotoxin in vivo: a potential
A I Chapoval1, S J Kamdar, S G Kremlev
1The Jackson Laboratory, Bar Harbor, Maine 04609, USA. aic@jax.org
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.
Insights
Colony-stimulating factor 1 (CSF-1) primes tissue mononuclear phagocytes (MNP) to enhance endotoxin-induced inflammatory mediator production. This priming increases sensitivity to lipopolysaccharide (LPS) by boosting interleukin-6 and tumor necrosis factor-alpha release from specific tissue-resident cells.
Area of Science:
- Immunology
- Cell Biology
- Pathophysiology
Background:
- Colony-stimulating factor 1 (CSF-1) is recognized for its role in priming mononuclear phagocytes (MNP) for inflammatory responses in vitro.
- The in vivo effects of CSF-1 on host sensitivity to endotoxic shock mediators remain less understood.
Purpose of the Study:
- To investigate whether CSF-1 administration in vivo sensitizes the host to increased production of endotoxic shock mediators, specifically tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6).
- To determine which cell types and tissues are affected by CSF-1 priming in response to lipopolysaccharide (LPS) challenge.
Main Methods:
- Mice were primed with CSF-1 via intravenous or intraperitoneal injection.
- Primed and control mice were challenged with lipopolysaccharide (LPS).
- Serum levels of IL-6 and TNF-alpha were measured.
- Peripheral blood leukocytes, spleen cells, and resident peritoneal cells (PC) were isolated and analyzed for cytokine release and mRNA expression (IL-6, TNF-alpha).
- mRNA expression in various tissues was also assessed.
Main Results:
- CSF-1-primed mice exhibited increased serum IL-6 and TNF-alpha levels after LPS challenge.
- Intraperitoneal CSF-1 administration led to maximal IL-6 increases.
- Resident peritoneal cells (PC) from CSF-1-primed mice constitutively released IL-6 and expressed IL-6 mRNA, while liver, lung, and kidney showed enhanced TNF-alpha mRNA expression post-LPS challenge.
- CSF-1 primes tissue MNP, not circulating MNP, to transcribe mRNA and release IL-6 and TNF-alpha.
Conclusions:
- CSF-1 plays a significant role in modulating host sensitivity to the pathophysiological effects of endotoxin.
- The priming effect of CSF-1 is specific to tissue-resident mononuclear phagocytes, influencing their response to LPS.
- These findings highlight CSF-1 as a key regulator in endotoxic shock pathways.