Role of Nitric Oxide in Depressed Lymphoproliferative Responses and Altered Cytokine Production Following Thermal Injury in Rats

Masson, Isabelle; Mathieu, Jacques; Nolland, Xavier-Bernard; Sousa, Martine De; Chanaud, Brigitte; Strzalko, S; Chancerelle, Yves; Kergonou, Jean-François; Giroud, Jean‐Paul; Florentin, I.

doi:10.1006/cimm.1998.1296

Cited by 29 publications

(21 citation statements)

References 53 publications

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“…SMTU treatment of normal spleen cells was without effect, although these cells released sizeable quantity of NO. This reinforces our previous findings that NO concentrations may exceed a threshold value to be immunosuppressive [4].…”

Section: Discussionsupporting

confidence: 92%

“…Taken altogether, the data described above, in conjunction with our previous findings [4,24], led us to propose a sequence of events schematized in Fig. 6, triggered by the overproduction of NO when spleen cells from burn-injured rats are exposed to an immune stimulus, and ending in post-burn immunosuppression.…”

Section: Discussionmentioning

confidence: 61%

“…Very recently, Paterson et al [39] demonstrated that burn injury in mice enhanced Toll-like receptor reactivity of macrophages and dendritic cells to lipopolysaccharide, leading to increased production of pro-inflammatory cytokines. We previously showed that IFNg is rapidly released after Con A stimulation of spleen cells from both normal and burned rats [4], suggesting that the macrophages were activated by the classical way and likely belonged to the M-1 type described by Mills et al [40] and characterized by NO-producing capacity.…”

Section: Discussionmentioning

confidence: 86%

“…The mechanisms underlying post-traumatic immune dysfunction are far from being elucidated. As we demonstrated before using thermal injury in rats as a model of trauma, an overproduction of nitric oxide (NO) by splenic macrophages is responsible for the collapse of T cell proliferative responses to polyclonal activators without inhibition of interleukin-2 (IL-2) and interferon gamma (IFNg) production [3,4]. Schwacha et al [5,6] confirmed and extended our findings as they showed that splenic macrophages from burned C57Bl/6 mice were in a hyperactive state through activation by IFNg and suppressed T cell proliferation through NO production.…”

Section: Introductionmentioning

confidence: 99%

“…Administration of iNOS inhibitors allowed to demonstrate that in vivo NO could induce suppression of specific immune responses against infectious pathogens and tumors with deleterious effects, but also against alloantigens and some autoantigens with beneficial effects [10,11]. In different experimental models, impairment of T lymphocyte responses to antigens or mitogens has been ascribed either to alterations in cytokine production including IL-2 [12 -15], to inhibition of T cell proliferation despite normal IL-2 release [16,17], or to induction of apoptosis in activated T cells [4,18,19]. Identification of molecular targets of NO inhibitory activity within lymphocytes is still limited.…”

Section: Introductionmentioning

confidence: 99%

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High levels of endogenous nitric oxide produced after burn injury in rats arrest activated T lymphocytes in the first G1 phase of the cell cycle and then induce their apoptosis

Mathieu

Chancerelle

Sousa

et al. 2005

Experimental Cell Research

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

High levels of endogenous nitric oxide produced after burn injury in rats arrest activated T lymphocytes in the first G1 phase of the cell cycle and then induce their apoptosis

Mathieu

Chancerelle

Sousa

et al. 2005

Experimental Cell Research

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MAP kinases differentially regulate the expression of macrophage hyperactivity after thermal injury

Alexander

Daniel

Chaudry

et al. 2004

Journal Cellular Physiology

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Thermal injury increases the capacity of macrophages (Mphi) to produce various inflammatory mediators, (i.e., Mphi hyperactivity), which is believed to be involved in the development of subsequent immunosuppression, sepsis, and multiple organ failure. The signal transduction pathways involved in the expression of Mphi hyperactivity post-burn, however, remain to be clearly elucidated. To study this C57BL/6 female mice were subjected to a 25% TBSA burn and splenic Mphis were isolated 7 days later. LPS-stimulated inflammatory mediator production and MAPK expression (P38 ERK 1/2 and JNK) were determined. Burn injury increased LPS-induced P38 MAPK, suppressed JNK activation and ERK 1/2 activation was unaltered. These changes in MAPK activation were paralleled by the increased production of PGE(2), TNF-alpha, IL-1beta, IL-6, and IL-10. Differential sensitivity to the inhibition of the MAPK pathways was observed with regard to the mediator evaluated and the presence or absence of burn injury. In general cytokine production in the burn group was in part resistant to the inhibition of a single MAPK pathway as compared with shams. Thus, burn injury increases cross-talk between the MAPKs pathways, suggesting that alterations MAPK activation and signal transduction contribute to the development Mphi hyperactivity post-injury.

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Nitric oxide contributes to the development of a post‐injury Th2 T‐cell phenotype and immune dysfunction

Daniel

Alexander

Hubbard

et al. 2006

Journal Cellular Physiology

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Severe injury induces immune dysfunction resulting in increased susceptibility to opportunistic infections. Previous studies from our laboratory have demonstrated that post-burn immunosuppression is mediated by nitric oxide (NO) due to the increased expression of macrophage inducible nitric oxide synthase (iNOS). In contrast, others suggest that injury causes a phenotypic imbalance in the regulation of Th1- and Th2 immune responses. It is unclear whether or not these apparently divergent mediators of immunosuppression are interrelated. To study this, C57BL/6 mice were subjected to major burn injury and splenocytes were isolated 7 days later and stimulated with antiCD3. Burn injury induced NO-mediated suppression of proliferative responses that was reversed in the presence of the NOS inhibitor L-monomethyl-L-arginine and subsequently mimicked by the addition of the NO donor, S-nitroso-N-acetyl-penicillamine (SNAP). SNAP also dose-dependently suppressed IFN-gamma and IL-2 (Th1), but not IL-4 and IL-10 (Th2) production. Delaying the addition of SNAP to the cultures by 24 h prevented the suppression of IFN-gamma production. The Th2 shift in immune phenotype was independent of cGMP and apoptosis. The addition of SNAP to cell cultures also induced apoptosis, attenuated mitochondrial oxidative metabolism and induced mitochondrial membrane depolarization. However, these detrimental cellular effects of NO were observed only at supra-physiologic concentrations (>250 microM). In conclusion, these findings support the concept that NO induces suppression of cell-mediated immune responses by selective action on Th1 T cells, thereby promoting a Th2 response.

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Role of Nitric Oxide in Depressed Lymphoproliferative Responses and Altered Cytokine Production Following Thermal Injury in Rats

Cited by 29 publications

References 53 publications

High levels of endogenous nitric oxide produced after burn injury in rats arrest activated T lymphocytes in the first G1 phase of the cell cycle and then induce their apoptosis

High levels of endogenous nitric oxide produced after burn injury in rats arrest activated T lymphocytes in the first G1 phase of the cell cycle and then induce their apoptosis

MAP kinases differentially regulate the expression of macrophage hyperactivity after thermal injury

Nitric oxide contributes to the development of a post‐injury Th2 T‐cell phenotype and immune dysfunction

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