Impaired induction of IL-10 expression in the lung following hemorrhagic shock
Departments of Surgery, University Health Network and University of Toronto, Toronto, Ontario, Canada. Shock
(Impact Factor: 3.05).
11/2004; 22(4):333-9. DOI: 10.1097/01.shk.0000136095.96306.08
The balance between pro- and anti-inflammatory cytokines is considered to be an important determinant of the magnitude of inflammation in a number of disease states. We previously showed that resuscitated hemorrhagic shock augmented LPS-induced release of proinflammatory molecules by alveolar macrophages (AM). In the present studies, we evaluated the expression and regulation of the counter inflammatory cytokine IL-10 in the lung using this model. We hypothesized that impaired up-regulation of IL-10 in shock/resuscitated animals might serve as a mechanism contributing to accentuated lung inflammation. In a rodent model, animals exposed to LPS alone exhibited enhanced IL-10 mRNA levels in lung tissue as well as in AM, but antecedent shock/resuscitation delayed and attenuated the LPS-induced IL-10 mRNA levels. The ability of shock to attenuate LPS-stimulated IL-10 was also seen in the protein levels. This effect correlated with an augmented expression of cytokine-induced neutrophil chemoattractant (CINC) mRNA. Shock/resuscitated animals given exogenous IL-10 had reduced proinflammatory response, as shown by decreased expression of CINC mRNA and decreased neutrophil sequestration in the lung. Shock/resuscitation plus LPS markedly reduced the transcription rate of IL-10 mRNA compared to LPS alone but did not affect IL-10 mRNA stability. Reduced IL-10 transcription was not caused solely by impaired nuclear translocation of STAT3 and Sp1/Sp3 transcription factors because LPS-induced nuclear translocation of these factors was augmented by antecedent shock. Considered together, these findings show that shock/resuscitation suppresses LPS-induced IL-10 expression by AM in the lung by inhibiting IL-10 gene transcription. Failed up-regulation of counter inflammatory cytokines may contribute to augmented organ dysfunction in trauma patients.
Available from: Michael Frink
- "Although IL-10 levels were increased in patients with MODS, studies have shown that elevated levels may contribute to augmented organ dysfunction in trauma patients . However, IL-10 failed to predict development of organ dysfunction in the present study. "
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ABSTRACT: Although therapeutic concepts of patients with major trauma have improved during recent years, organ dysfunction still remains a frequent complication during clinical course in intensive care units. It has previously been shown that cytokines are upregulated under stress conditions such as trauma or sepsis. However, it is still debatable if cytokines are adequate parameters to describe the current state of trauma patients. To elucidate the relevance of cytokines, we investigated if cytokines predict development of multiple organ dysfunction syndrome (MODS) or outcome.
A total of 143 patients with an injury severity score >or= 16, between 16 and 65 years, admitted to the Hannover Medical School Level 1 Trauma Center between January 1997 and December 2001 were prospectively included in this study. Marshall Score for MODS was calculated for at least 14 days and plasma levels of TNF-alpha, IL-1beta, IL-6, IL-8 and IL-10 were measured. To determine the association between cytokine levels and development of MODS the Spearman rank correlation coefficient was calculated and logistic regression and analysis were performed.
Patients with MODS had increased plasma levels of IL-6, IL-8 and IL-10. IL-6 predicted development of MODS with an overall accuracy of 84.7% (specificity: 98.3%, sensitivity: 16.7%). The threshold value for development of MODS was 761.7 pg/ml and 2176.0 pg/ml for mortality during the in patient time.
We conclude that plasma IL-6 levels predict mortality and that they are a useful tool to identify patients who are at risk for development of MODS.
Available from: uni-duisburg-essen.de
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ABSTRACT: After hemorrhagic shock and during sepsis, antigen-presenting cells loose the capacity to respond to bacteria or bacterial products with the secretion of pro-inflammatory cytokines. This malfunction of antigen-presenting cells like macrophages and dendritic cells is associated with the development of immunosuppression and might lead to multi-organ failure and death. GM-CSF is a cytokine that is known to modulate the cytokine secretion of antigen-presenting cells and additionally acts as growth factor on myeloid cells. In the present study, the capacity of GM-CSF to restore the secretion of pro-inflammatory cytokines by macrophages and dendritic cells was investigated in animal models for hemorrhagic shock and polymicrobial sepsis. Additionally, it was tested in vitro, whether GM-CSF might mediate the differentiation of competent dendritic cells from bone marrow during sepsis.
GM-CSF restored the suppressed LPS-induced TNF-α release from the splenic macrophages after hemorrhagic shock and during sepsis up to levels observed for the respective LPS-stimulated cells from sham mice. GM-CSF partially but not completely restored the suppressed LPS-induced TNF-α production from the peritoneal macrophages after hemorrhagic shock. The GM-CSF-mediated restoration of the LPS-induced TNF-α secretion by peritoneal macrophages was verified on the level of IκBα phosphorylation. In addition GM-CSF effects were also associated with increased levels of the activated forms of the signaling molecules P38MAPK and ERK1/2, possibly suggesting an involvement of one of these MAPK in the stimulatory effects of GM-CSF. In contrast, GM-CSF was inefficient in restoring the LPS-induced cytokine response by dendritic cells from septic animals. Analyses of the phenotype of dendritic cells that differentiated from bone marrow progenitors of septic mice in the presence of GM-CSF showed that these dendritic cells display an aberrant cytokine response and fail to polarize Th lymphocytes towards Th1. This malfunction of in vitro generated dendritic cells from septic mice is associated with an increased secretion of IL-10 in response to immunostimulatory bacterial oligonucleotides and resembles the deviated cytokine response from splenic dendritic cells during sepsis. The absence of IL-10 or LPS during the GM-CSF-dependent differentiation of dendritic cells suggests that another mechanism was responsible for the development of the abnormal phenotype from BMDC from septic mice. A reduced population of CD4+ dendritic cell progenitors with so far unknown function was found in the bone marrow of septic mice and might play a role in the aberrant differentiation of dendritic cells during sepsis. In summary, GM-CSF therapy might reinforce the macrophages’ antibacterial defence mechanisms during hemorrhagic shock and sepsis-associated immunosuppression. However, differentiation of dendritic cells from bone marrow during sepsis might result in an aberrant phenotype of dendritic cells that prevent the development of a protective Th1 response and, thereby, further aggravates immunosuppression.
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ABSTRACT: Interleukin-10 (IL-10) activates a diverse array of functional responses in mononuclear phagocytes. Functional IL-10 receptor (IL-10R) complexes are tetramers consisting of two IL-10R1 polypeptide chains and two IL-10R2 chains. Binding of IL-10 to the extracellular domain of IL-10R1 activates phosphorylation of the receptor-associated Janus tyrosine kinases, JAK1 and Tyk2. These kinases then phosphorylate specific tyrosine residues (Y446 and Y496) on the intracellular domain of the IL-10R1 chain. Once phosphorylated, these tyrosine residues (and their flanking peptide sequences) serve as temporary docking sites for the latent transcription factor, STAT3 (signal transducer and activator of transcription-3). STAT3 binds to these sites via its SH2 (Src homology 2) domain, and is, in turn, tyrosine-phosphorylated by the receptor-associated JAKs. It then homodimerizes and translocates to the nucleus where it binds with high affinity to STAT-binding elements (SBE) in the promoters of various IL-10-responsive genes. One of these genes, SOCS-3 (Suppressor of Cytokine Signaling-3) is a member of a newly identified family of genes that inhibit JAK/STAT-dependent signaling. Moreover, the ability of IL-10 to induce de novo synthesis of SOCS-3 in monocytes correlates with its ability to inhibit expression of many genes in these cells, including endotoxin-inducible cytokines such as tumor necrosis factor-alpha (TNF-alpha) and IL-1. Thus, the ability of IL-10 to inhibit gene expression in monocytes is associated with its ability to rapidly induce synthesis of SOCS-3.
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