Critical Role of Kupffer Cell-Derived IL-10 for Host Defense in Septic Peritonitis

Emmanuilidis, Klaus; Weighardt, Heike; Maier, Stefan; Gerauer, Klaus; Fleischmann, Tanja; Zheng, Xin Xiao; Hancock, Wayne W.; Holzmann, Bernhard; Heidecke, Claus–Dieter

doi:10.4049/jimmunol.167.7.3919

Cited by 83 publications

(65 citation statements)

References 59 publications

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“…Interestingly, the massive increase in IL-10 observed in STAT-1 -/-mice appears to be confined to circulating blood cells, and not tissue macrophages. Previous work documents Kupffer cells as important in LPS-stimulated IL-10 production [13], but our results suggest that blood monocytes circulating through the organs are responsible for IL-10 production during an acute systemic release of LPS. The different experimental systems employed in these studies likely explain the contrasting results, and more work will need to be done to better understand why cells in different stages of differentiation appear to differentially respond to a simulated systemic gram-negative infection.…”

Section: Discussioncontrasting

confidence: 79%

“…In vitro, IL-10 is produced by monocytes and macrophages following exposure to LPS [9], and its mechanism of action includes down-regulating the production of pro-inflammatory cytokines such as IFN-c, as well as repressing IFN-c-mediated signal transducer and activator of transcription (STAT)-1 activation through induction of the suppressor of cytokine signaling family of proteins [12]. The importance of IL-10 in controlling proinflammatory cytokine release is evidenced by studies demonstrating increased mortality among mice with neutralized or deficient IL-10 following LPS challenge [13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

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STAT‐1‐mediated repression of monocyte interleukin‐10 gene expression in vivo

et al. 2006

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There have been substantial advances in understanding the events that regulate gene expression at the cellular and molecular level; however, there has been limited progress integrating this information to understand how biological systems function in vivo. For example, the anti‐inflammatory cytokine IL‐10 is thought to down‐regulate the effects of the pro‐inflammatory cytokine IFN‐γ on monocyte activation following LPS stimulation. However, the often‐postulated reciprocal regulation of IL‐10 gene expression by IFN‐γ has not been studied in vivo. Here we demonstrate that the regulation of IL‐10 gene expression has at least two phases following challenge with LPS or a gram‐negative organism. In C57BL/6 mice, early IL‐10 induction occurs independently of STAT‐1, while a delayed active repression of IL‐10 gene expression is critically dependent on STAT‐1, but only partially dependent upon IFN‐α/β and IFN‐γ. This in vivo IL‐10 production comes from blood monocytes, but not tissue macrophages, and cannot be reproduced in vitro. This study provides new insights into the regulation of IL‐10 following challenge with a gram‐negative organism, and highlights the importance of studying these cytokine regulatory pathways in vivo.

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Section: Discussioncontrasting

confidence: 79%

Section: Introductionmentioning

confidence: 99%

STAT‐1‐mediated repression of monocyte interleukin‐10 gene expression in vivo

et al. 2006

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“…Therefore, it appears conceivable that, during septic peritonitis, endothelial cells contribute to systemic IL-6 and CXCL1 levels, whereas IL-10 and IL-12p40 may be released into the circulation by myeloid cells. Consistent with this notion, previous work showed that hepatic Kupffer cells are the major source of systemic IL-10 in murine septic peritonitis (12), and Kupffer cell density was found to be comparable among WT, Myd88 LSL/LSL , and Myd88 MYEL mice (Supplemental Fig. 1E).…”

Section: Myd88 Expression In Both Myeloid and Nonmyeloid Cells Is Reqsupporting

confidence: 70%

Cutting Edge: Divergent Cell-Specific Functions of MyD88 for Inflammatory Responses and Organ Injury in Septic Peritonitis

Gais

Reim

Jusek

et al. 2012

The Journal of Immunology

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Although global MyD88 deficiency attenuates lethal inflammation in sepsis, cell-specific functions of MyD88 remain largely unknown. Using mice with selective expression of MyD88 in myeloid cells (Myd88MYEL), we show that, during polymicrobial septic peritonitis, both myeloid and nonmyeloid cells contribute to systemic inflammation, whereas myeloid cell MyD88 was sufficient to fully establish the peritoneal cytokine response. Importantly, Myd88MYEL mice developed markedly aggravated liver injury that was linked to impaired upregulation of cellular inhibitor of apoptosis protein 2 and an excessive production of TNF-α. Upregulation of inducible cAMP early repressor (ICER), a known transcriptional repressor of the Tnfa gene, was impaired in Myd88MYEL mice. Moreover, Myd88MYEL mice showed enhanced transcription of the Tnfa gene and an excessive production of CCL3, which is also negatively regulated by ICER, but they had normal levels of CXCL1, which is expressed in an ICER-independent manner. Together, these findings suggest a novel protective role for nonmyeloid cell MyD88 in attenuating liver injury during septic peritonitis.

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“…In addition, high systemic IL-10 levels in CCR2 antibody-treated mice may also contribute to IL-10 levels at local sites like peritoneal cavity. Previous work has shown that systemic IL-10 levels in the CASP model of septic peritonitis are mostly derived from hepatic Kupffer cells [41], suggesting that this major population of tissue macrophages may also be involved in the effects of CCR2 blockade.…”

Section: Discussionmentioning

confidence: 99%

CC chemokine receptor 2 regulates leukocyte recruitment and IL‐10 production during acute polymicrobial sepsis

Feterowski

Mack²,

Weighardt

et al. 2004

Eur J Immunol

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Chemokine receptors are important for recruiting leukocytes to sites of infection and may contribute to immune cell activation. The present study investigated the role of the chemokine receptor CCR2 in polymicrobial septic peritonitis. The results showed that peritoneal production of the CCR2 ligands CCL2 and CCL12 in septic mice was largely independent of the common Toll-like receptor signaling adaptor MyD88. Antibody blockade of CCR2 reduced the recruitment of macrophages and neutrophils to the infected peritoneal cavities of both wild-type and MyD88-deficient mice, suggesting that CCR2 engagement contributes to the MyD88-independent cellular response against polymicrobial septic peritonitis. Notably, administration of blocking CCR2 antibodies markedly increased local and systemic IL-10 levels in septic wild-type mice, whereas IL-10 was not detected in MyD88-deficient mice irrespective of whether CCR2 was blocked or not. Inhibition of CCR2 directly augmented Tolllike receptor-induced IL-10, but not TNF and IL-6, production of macrophages in vitro. Concomitant with enhanced IL-10 production, CCR2 blockade caused impaired bacterial clearance and aggravated kidney injury in wild-type, but not MyD88-null mice. These results indicate that CCR2 engagement modulates the innate immune response to polymicrobial septic peritonitis by both MyD88-dependent and -independent processes and suggest that a major function of CCR2 in sepsis is to attenuate IL-10 production and IL-10-mediated suppression of host defense.

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Critical Role of Kupffer Cell-Derived IL-10 for Host Defense in Septic Peritonitis

Cited by 83 publications

References 59 publications

STAT‐1‐mediated repression of monocyte interleukin‐10 gene expression in vivo

STAT‐1‐mediated repression of monocyte interleukin‐10 gene expression in vivo

Cutting Edge: Divergent Cell-Specific Functions of MyD88 for Inflammatory Responses and Organ Injury in Septic Peritonitis

CC chemokine receptor 2 regulates leukocyte recruitment and IL‐10 production during acute polymicrobial sepsis

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