Interferon-?? Production Is Suppressed in Thermally Injured Mice: Decreased Production of Regulatory Cytokines and Corresponding Receptors

Toliver‐Kinsky, Tracy; Varma, Tushar K.; Chen, Lin; Herndon, David N.; Sherwood, Edward R.

doi:10.1097/00024382-200210000-00006

Cited by 45 publications

(33 citation statements)

References 33 publications

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“…The IL-18 response after bacterial infection might be closely related to IFN-␥ production and thereby to the host defense mechanism, particularly regarding cellular immunity against postburn bacterial infections. Toliver-Kinsky et al (51,52) studied the mechanism of immune suppression after burn injury and claimed that IFN-␥ production was suppressed after P. aeruginosa infection; but they used heatkilled P. aeruginosa, and we have also shown similar results using heat-killed P. aeruginosa. Horvat et al (27) and Parmely et al (28) have demonstrated that some P. aeruginosa strains secrete alkaline protease and elastase and thereby inactivate recombinant IFN-␥.…”

Section: Discussionsupporting

confidence: 63%

Restoration of Natural IgM Production from Liver B Cells by Exogenous IL-18 Improves the Survival of Burn-Injured Mice Infected with Pseudomonas aeruginosa

Kinoshita

Shinomiya²,

Ono

et al. 2006

The Journal of Immunology

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Pseudomonas aeruginosa is the most common bacterium of postburn infection. In the present study we investigated the immune mechanism of susceptibility to this type of postburn infection and also examined the efficacy of IL-18 treatment. C57BL/6 mice were challenged with P. aeruginosa on day 7 after burn injury. Although the burn-injured mice showed a poor survival rate after bacterial challenge, they retained their IFN-γ production. The burned mice showed lower serum IgM levels and a poor IgM response following P. aeruginosa challenge in comparison with the sham mice, whereas IL-18 treatment after burn injury (alternate day injections for 1 wk) greatly improved the serum IgM levels, which are P. aeruginosa-independent natural IgM before bacterial challenge, thereby increasing the survival rate after the challenge. IL-18 treatment also induced specific IgM to P. aeruginosa in the sera 5 days after bacterial challenge in the burned mice. Interestingly, CD43+CD5−CD23−B220dim cells, namely B-1b cells, increased in the liver after the IL-18 treatment and were found to actively produce IgM in vitro without any additional stimulation. Furthermore, the IL-18 treatment up-regulated the neutrophil count and the C3a levels in the blood as a result of the increased IgM level, which may thus play a critical role in the opsonization and elimination of any invading bacteria. IL-18 treatment for the burned mice and their resultant natural IgM production were thus found to strengthen the host defense against P. aeruginosa infection.

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Section: Discussionsupporting

confidence: 63%

Restoration of Natural IgM Production from Liver B Cells by Exogenous IL-18 Improves the Survival of Burn-Injured Mice Infected with Pseudomonas aeruginosa

Kinoshita

Shinomiya²,

Ono

et al. 2006

The Journal of Immunology

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“…IFN-g and IL-12 are normally elevated in response to systemic bacterial challenge. 27,28 The significance of low IFN-g and IL-12 concentrations in blood and peritoneal fluid following CLP is not completely clear but further brings into question the functional role of bacteremia in CLP-induced death. However, Echtenacher et al 29 showed that neutralization of IFN-g and IL-12 does not alter mortality in mice exposed to CLP.…”

Section: Discussionmentioning

confidence: 99%

Mice depleted of CD8+ T and NK cells are resistant to injury caused by cecal ligation and puncture

Sherwood

Enoh

Murphey

et al. 2004

Laboratory Investigation

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We previously showed that beta 2 microglobulin knockout mice depleted of NK cells by treatment with antiasialoGM1 (b2MKO/aAsGM1 mice) are resistant to sepsis caused by cecal ligation and puncture (CLP). b2MKO mice possess multiple immunological defects including depletion of CD8 þ T cells. This study was designed to determine the contribution of CD8 þ T and NK cell deficiency to the resistance of b2MKO/aAsGM1 mice to CLPinduced injury. b2MKO/aAsGM1 mice and CD8 knockout mice treated with anti-asialoGM1 (CD8KO/aAsGM1 mice) survived significantly longer than wild-type mice following CLP. Improved long-term survival was also observed in wild-type mice rendered CD8 þ T/NK cell-deficient by treatment with both anti-CD8a and antiasialoGM1. Blood gas analysis and body temperature measurements showed that CD8 þ T and NK cell-deficient mice have significantly reduced metabolic acidosis and less hypothermia compared to control mice at 18 h after CLP. CD8 þ T/NK cell-deficient mice also showed an attenuated proinflammatory response as indicated by decreased expression of mRNAs for IL-1, IL-6 and MIP-2 in spleen and heart. IL-6, KC and MIP-2 levels in blood and peritoneal fluid were also significantly decreased CD8 þ T/NK cell-deficient mice compared to controls. CD8 þ T/NK cell-deficient mice exhibited decreased bacterial concentrations in blood, but not in peritoneal fluid or lung, compared to wild-type controls. These data show that mice depleted of CD8 þ T and NK cells exhibit survival benefit, improved physiologic function and an attenuated proinflammatory response following CLP that is comparable to b2M/aAsGM1 mice. We previously demonstrated that b2 microglobulin knockout mice that were depleted of natural killer (NK) cells by treatment with anti-asialoGM1 (b2MKO/aAsGM1 mice) are resistant to systemic injury caused by cecal ligation and puncture (CLP). 1 Specifically, b2MKO/aAsGM1 mice exhibit improved survival, less metabolic acidosis, reduced hypothermia and better hemodynamic function compared to control mice following CLP. 1,2 These improvements in physiological function are associated with attenuation of the CLP-induced proinflammatory response.b2MKO/aAsGM1 mice have multiple immunological defects including an absence of CD8 þ T, natural killer (NK) and natural killer T (NKT) cells as well as deficient expression of the class I major histocompatability complex (MHC-I) and CD1 molecules. 1,3-5 One of our goals is to determine which of these immunological alterations confers resistance to the CLP-induced sepsis syndrome. We previously showed that adoptive transfer of CD8 þ T and NK cells into b2MKO/aAsGM1 mice will re-establish CLP-induced mortality. 1 In addition, we showed improved post-CLP survival in mice that are deficient of both CD8 þ T and NK cells. Based on this observation, we hypothesize that CD8 þ T and NK cell depletion contributes to the resistance of b2MKO/aAsGM1 mice to CLP-induced injury. To test this hypothesis, we directly compared CLP-induced mortality in b2MKO/aAsGM1 mice and CD8 þ T/NK cell-d...

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“…This syndrome is often termed immunoparalysis or postinflammatory immunosuppression and is characterized by decreased production of gamma interferon (IFN-␥) and interleukin-12 (IL-12) as well as increased secretion of the antiinflammatory cytokine IL-10 in response to an infectious challenge. Some researchers have proposed that the state of endotoxin (lipopolysaccharide [LPS]) tolerance is a model of immunoparalysis because LPS-tolerant animals exhibit a pattern of cytokine production that is nearly identical to that observed during postinflammatory immunosuppression (10,28,31). LPS tolerance is induced by exposure to sublethal doses of LPS, which results in a suppressed proinflammatory response and improved survival after challenge with a normally lethal dose of LPS (4,15).…”

mentioning

confidence: 99%

“…IFN-␥ production is induced by the macrophage-and dendritic cell-derived cytokines IL-12, IL-15, and IL-18, which are produced after engagement of pattern recognition receptors by bacterial products such as LPS. Suppressed secretion of these cytokines is reported to be a hallmark of injury-induced immunoparalysis (20,28). In contrast, elevated levels of IL-10 may suppress antimicrobial immunity and render the host more susceptible to infections (28).…”

mentioning

confidence: 99%

Endotoxin Priming Improves Clearance ofPseudomonas aeruginosain Wild-Type and Interleukin-10 Knockout Mice

Varma

Durham²,

Murphey

et al. 2005

Infect Immun

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Endotoxin (lipopolysaccharide [LPS]) tolerance is an altered state of immunity caused by prior exposure to LPS, in which production of many cytokines, including gamma interferon (IFN-␥) and interleukin-12 (IL-12), are reduced but secretion of the anti-inflammatory cytokine IL-10 is increased in response to a subsequent LPS challenge. This pattern of cytokine production is also characteristic of postinflammatory immunosuppression. Therefore, we hypothesized that LPS-primed mice would exhibit an impaired ability to respond to systemic infection with the opportunistic pathogen Pseudomonas aeruginosa. We further hypothesized that depletion of IL-10 would reverse the endotoxin-tolerant state. To test this hypothesis, systemic clearance of Pseudomonas aeruginosa was measured for LPS-primed wild-type and IL-10-deficient mice. LPS-primed wild-type mice exhibited significant suppression of LPS-induced IFN-␥ and IL-12 but increased IL-10 production in blood and spleen compared to levels exhibited by saline-primed wild-type mice. The suppressed production of IFN-␥ and IL-12 caused by LPS priming was ablated in the spleens, but not blood, of IL-10 knockout mice. LPS-primed wild-type mice cleared Pseudomonas aeruginosa from lungs and blood more effectively than saline-primed mice. LPS-primed IL-10-deficient mice were particularly efficient in clearing Pseudomonas aeruginosa after systemic challenge. These studies show that induction of LPS tolerance enhanced systemic clearance of Pseudomonas aeruginosa and that this effect was augmented by neutralization of IL-10.

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Interferon-?? Production Is Suppressed in Thermally Injured Mice: Decreased Production of Regulatory Cytokines and Corresponding Receptors

Cited by 45 publications

References 33 publications

Restoration of Natural IgM Production from Liver B Cells by Exogenous IL-18 Improves the Survival of Burn-Injured Mice Infected with Pseudomonas aeruginosa

Restoration of Natural IgM Production from Liver B Cells by Exogenous IL-18 Improves the Survival of Burn-Injured Mice Infected with Pseudomonas aeruginosa

Mice depleted of CD8+ T and NK cells are resistant to injury caused by cecal ligation and puncture

Endotoxin Priming Improves Clearance ofPseudomonas aeruginosain Wild-Type and Interleukin-10 Knockout Mice

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