Polymicrobial Sepsis but Not Low-Dose Endotoxin Infusion Causes Decreased Splenocyte IL-2/IFN-γ Release While Increasing IL-4/IL-10 Production

Ayala, Alfred; Deol, Zoe K.; Lehman, Donna L.; Herdon, Crystal D.; Chaudry, Irshad H.

doi:10.1006/jsre.1994.1092

Cited by 148 publications

(101 citation statements)

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“…Experimental sepsis models demonstrate similar findings. Ayala et al (52)(53)(54) showed in several reports that 24 h after CLP-induced sepsis, the capacity of septic mouse splenic/peritoneal macrophages to release cytokines was diminished. Specifically, ex vivo stimulation of these cells resulted in suppressed production of IL-2, IFN-␥, and IL-6 while IL-4 and IL-10 synthesis was enhanced after LPS/concanavalin stimulus.…”

Section: Discussionmentioning

confidence: 99%

Circulating Cytokine/Inhibitor Profiles Reshape the Understanding of the SIRS/CARS Continuum in Sepsis and Predict Mortality

Osuchowski

Welch

Siddiqui

et al. 2006

The Journal of Immunology

469

379

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Mortality in sepsis remains unacceptably high and attempts to modulate the inflammatory response failed to improve survival. Previous reports postulated that the sepsis-triggered immunological cascade is multimodal: initial systemic inflammatory response syndrome (SIRS; excessive pro-, but no/low anti-inflammatory plasma mediators), intermediate homeostasis with a mixed anti-inflammatory response syndrome (MARS; both pro- and anti-inflammatory mediators) and final compensatory anti-inflammatory response syndrome (CARS; excessive anti-, but no/low proinflammatory mediators). To verify this, we examined the evolution of the inflammatory response during the early phase of murine sepsis by repetitive blood sampling of septic animals. Increased plasma concentrations of proinflammatory (IL-6, TNF, IL-1β, KC, MIP-2, MCP-1, and eotaxin) and anti-inflammatory (TNF soluble receptors, IL-10, IL-1 receptor antagonist) cytokines were observed in early deaths (days 1–5). These elevations occurred simultaneously for both the pro- and anti-inflammatory mediators. Plasma levels of IL-6 (26 ng/ml), TNF-α (12 ng/ml), KC (33 ng/ml), MIP-2 (14 ng/ml), IL-1 receptor antagonist (65 ng/ml), TNF soluble receptor I (3 ng/ml), and TNF soluble receptor II (14 ng/ml) accurately predicted mortality within 24 h. In contrast, these parameters were not elevated in either the late-deaths (day 6–28) or survivors. Surprisingly, either pro- or anti-inflammatory cytokines were also reliable in predicting mortality up to 48 h before outcome. These data demonstrate that the initial inflammatory response directly correlates to early but not late sepsis mortality. This multifaceted response questions the use of a simple proinflammatory cytokine measurement for classifying the inflammatory status during sepsis.

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Section: Discussionmentioning

confidence: 99%

Circulating Cytokine/Inhibitor Profiles Reshape the Understanding of the SIRS/CARS Continuum in Sepsis and Predict Mortality

Osuchowski

Welch

Siddiqui

et al. 2006

The Journal of Immunology

469

379

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“…However, the mechanisms by which C5a is regulated in sepsis remain unclear. Proinflammatory cytokines contribute to an overwhelming inflammatory immune response in the early phase of sepsis, whereas anti-inflammatory cytokines are involved in the late-phase immune response [6,18,19]. Based on these findings, it is conceivable that the cytokine network interacts with the complement system in regulating immune responses in sepsis.…”

Section: Introductionmentioning

confidence: 99%

IFN‐γ‐producing NKT cells exacerbate sepsis by enhancing C5a generation via IL‐10‐mediated inhibition of CD55 expression on neutrophils

Kim

Ahn

et al. 2014

Eur J Immunol

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A role for NKT cells has been implicated in sepsis, but the mechanism by which NKT cells contribute to sepsis remains unclear. Here, we examined WT and NKT-cell-deficient mice of C57BL/6 background during cecal ligation and puncture-induced sepsis. The levels of C5a, IFN-γ, and IL-10 were higher in the serum and peritoneal fluid of WT mice than in those of CD1d −/− mice, while the mortality rate was lower in CD1d −/− mice than in WT mice. C5a blockade decreased mortality of WT mice during sepsis, whereas it did not alter that of CD1d −/− mice. As assessed by intracellular staining, NKT cells expressed IFN-γ, while neutrophils expressed IL-10. Upon coculture, IL-10-deficient NKT cells enhanced IL-10 production by WT, but not IFN-γR-deficient, neutrophils. Meanwhile, CD1d −/− mice exhibited high CD55 expression on neutrophils during sepsis, whereas those cells from WT mice expressed minimal levels of CD55. Recombinant IL-10 administration into CD1d −/− mice reduced CD55 expression on neutrophils. Furthermore, adoptive transfer of sorted WT, but not IFN-γ-deficient, NKT cells into CD1d −/− mice suppressed CD55 expression on neutrophils, but increased IL-10 and C5a levels. Taken together, IFN-γ-producing NKT cells enhance C5a generation via IL-10-mediated inhibition of CD55 expression on neutrophils, thereby exacerbating sepsis.Keywords: C5a r IFN-γ r Neutrophils r NKT cell r Sepsis Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionNKT cells are a distinct T-cell subset characterized by the expression of natural killer receptors and semi-invariant TCRs. These cells recognize glycolipids presented by CD1d, an MHC class I-like Correspondence: Dr. Doo Hyun Chung e-mail: doohyun@snu.ac.kr protein expressed by APCs [1]. During bacterial infection, TCRs on NKT cells directly recognize glycolipids derived from certain Gramnegative bacterial membranes [2,3] and can be activated by innate cytokines secreted by dendritic cells that have been activated by microorganisms [2,4]. Furthermore, LPS-mediated engagement of TLR4 directly activates NKT cells in terms of differential * These authors contributed equally to this work. Eur. J. Immunol. 2014Immunol. . 44: 2025Immunol. -2035 cytokine production, thereby regulating immune diseases [5]. These findings suggest that NKT cells, activated during immune responses against bacteria, regulate bacteria-mediated pathologic processes such as sepsis. Sepsis is a complex inflammatory dysregulation that causes multiple organ dysfunction and coagulopathy, often resulting in death [6,7]. Several studies have demonstrated that NKT cells promote LPS-or cecal ligation and puncture (CLP)-induced sepsis in mice through the production of . Consistent with these findings, two independent studies have demonstrated that treatment of C57BL/6 mice with anti-CD1d antibody enhances survival rates during CLP-induced sepsis [11,12], suggesting that NKT-cell-mediated promotion of sepsis depends on an interaction between CD1d and TCR...

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“…Studies from our laboratory (25) and a number of others (26)(27)(28)(29)(30) have shown that in late sepsis or after traumatic injury or shock, there is a decrease in splenic lymphocyte IL-2 and interferon (IFN)-γ release capacity that is associated with an increased ability to produce the antiinflammatory cytokines IL-4 and IL-10.…”

Section: Active Suppression Via Anti-inflammatory Mediator Releasementioning

confidence: 97%

“…Studies in our own laboratory indicate splenocytes isolated from mice after the onset of sepsis (25) or hemorrhagic shock (47) exhibited an enhanced capacity to produce IL-4. However, unlike IL-10, little evidence of this cytokine's presence in the shocked/septic mouse's circulation has been collected (48).…”

Section: Il-4-thementioning

confidence: 99%

“…These subpopulations are defined primarily by their propensity to produce either cytokines like IL-2 and IFN-γ that support the development of a cell mediated immune response, or cytokines such as IL-4, IL-5, IL-6, IL-10, and IL-13 that, while driving humoral immunity, generally suppress cell-mediated immunity (94)(95)(96). Several investigators looking at divergent models of injury have since reported evidence of the development of a "shift" in the injured/infected animals'/ patients' T-helper cell response to one that seems to be dominated by the immune suppressive (Th2) lymphoid phenotype in conditions of burn (97)(98)(99)(100)(101)(102), hemorrhage (47,103), and sepsis (25,43,104). Interestingly, Zedler et al (105) indicated that such "shifting" between immune enhancing and immune suppressive (Th1 to Th2) T-cell phenotypes also may be evident in the CD8 + T-lymphocyte population of critically injured patients.…”

Section: Potential Regulatory Cell Populations Contributing To Resolumentioning

confidence: 99%

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Mechanisms of immune resolution

Ayala

Chung

Grutkoski

et al. 2003

Critical Care Medicine

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Initially after injury, the innate/proinflammatory and some aspects of the acquired immune response are up-regulated to maintain a defense against foreign pathogens, clear tissue debris present at the wound site, and orchestrate aspects of tissue remodeling, cell proliferation and angiogenic process, associated with the wound response. However, for proper wound healing to progress, this initial inflammatory response has to be regulated or shut down so as to allow for the reestablishment of matrix, recellularization, and tissue remodeling. Inability to properly resolve the extent of innate/ acquired response at a site of injury can lead to poor wound healing, immune suppression, and recurrent infectious episodes. This review attempts to summarize information on regulatory mechanisms that are thought to be involved in controlling/resolving innate or acquired immune responses so as to provide a framework for use in thinking about the impact these processes and their manipulation may have on wound healing and its potential management.

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Polymicrobial Sepsis but Not Low-Dose Endotoxin Infusion Causes Decreased Splenocyte IL-2/IFN-γ Release While Increasing IL-4/IL-10 Production

Cited by 148 publications

References 0 publications

Circulating Cytokine/Inhibitor Profiles Reshape the Understanding of the SIRS/CARS Continuum in Sepsis and Predict Mortality

Circulating Cytokine/Inhibitor Profiles Reshape the Understanding of the SIRS/CARS Continuum in Sepsis and Predict Mortality

IFN‐γ‐producing NKT cells exacerbate sepsis by enhancing C5a generation via IL‐10‐mediated inhibition of CD55 expression on neutrophils

Mechanisms of immune resolution

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