HEAT SHOCK PROTEIN 72 SUPPRESSES MACROPHAGE TNFα PRODUCTION BY INHIBITION OF NFB INTRANUCLEAR TRANSLOCATION

Meng, Xianzhong; Shames, B. D.; Ao, Lihua; Meldrum, Daniel R.; Chan, Danny; Banerjee, A.; Harken, Alden H.

doi:10.1097/00024382-199906001-00139

Cited by 3 publications

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“…The inhibitory effects of heat-shock on LPS-induced iNOS production in astrocytes, macrophages and other cell types are mainly mediated by expression of Hsp70 [24,25]. In addition, it has been well studied that over-expression of Hsp70 protects rat pancreatic islet b-cells against IL-1b stimulation and blocks TNF-a production in macrophage [26,27]. These findings suggest that induction of Abbreviations: Hsp70, heat shock protein 70; TRAF6, tumor necrosis factor receptor-associated factor 6; LPS, lipopolysaccharide; NF-jB, nuclear factor-jB; IjBa, inhibitor of NF-jB a; IKK, IjB kinase; MAPKs, mitogen-activated protein kinases; JNK, c-Jun N-terminal kinase; iNOS, inducible nitric oxide synthase; COX-2, cyclooxygenase-2 Hsp70 may protect the host by regulating LPS-induced production of cytokines in macrophages.…”

Section: Introductionmentioning

confidence: 99%

Hsp70 inhibits lipopolysaccharide‐induced NF‐κB activation by interacting with TRAF6 and inhibiting its ubiquitination

et al. 2006

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Inducible heat shock protein 70 (Hsp70) is one of the most important HSPs for maintenance of cell integrity during normal cellular growth as well as pathophysiological conditions. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is a crucial signaling transducer that regulates a diverse array of physiological and pathological processes and is essential for activating NF-jB signaling pathway in response to bacterial lipopolysaccharide (LPS). Here we report a novel mechanism of Hsp70 for preventing LPS-induced NF-jB activation in RAW264.7 macrophage-like cells. Our results show that Hsp70 can associate with TRAF6 physically in the TRAF-C domain and prevent TRAF6 ubiquitination. The stimulation of LPS dissociates the binding of Hsp70 and TRAF6 in a time-dependent manner. Hsp70 inhibits LPS-induced NF-jB signaling cascade activation in heat-shock treated as well as Hsp70 stable transfected RAW264.7 cells and subsequently decreases iNOS and COX-2 expression. Two Hsp70 mutants, Hsp70DC(1-428aa) with N-terminal ATPase domain and Hsp70C(428-642aa) with C-terminal domain, lack the ability to influence TRAF6 ubiquitination and TRAF6-triggered NF-jB activation. Taken together, these findings indicate that Hsp70 inhibits LPS-induced NF-jB activation by binding TRAF6 and preventing its ubiquitination, and results in inhibition of inflammatory mediator production, which provides a new insight for analyzing the effects of Hsp70 on LPS-triggered inflammatory signal transduction pathways.

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Section: Introductionmentioning

confidence: 99%

Hsp70 inhibits lipopolysaccharide‐induced NF‐κB activation by interacting with TRAF6 and inhibiting its ubiquitination

et al. 2006

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“…In whole animals, treatment with arsenite, which induces a HSR, blocked endotoxin‐induced NOS2 expression in lung (Hauser et al, 1996), and hyperthermia prevented NOS2 induction in brain following intrastriatal injection of cytokines and LPS (Heneka et al, 2000). In addition to NOS2, the HSR decreased expression of other inflammatory genes which are implicated in the development of neurodegenerative diseases, including the RANTES (regulated on activation of normal T‐cell‐expressed and secreted) chemokine (Ayad et al, 1998), the pro‐inflammatory cytokines IL1‐β (Simon et al, 1995; Housby et al, 1999) and tumor necrosis factor‐α (TNF‐α) (Snyder et al, 1992; Meng et al, 1999), and the intercellular adhesion molecule‐1 (ICAM1) (Housby et al, 1999). The exact mechanisms by which the HSR prevents inflammatory gene expression are not yet known, but studies demonstrating that the HSR causes upregulation of IkBα expression (Feinstein et al, 1996, 1997; DeMeester et al, 1997), and the presence of a consensus binding site for the HS transcription factor HSF1 within the IkBα promoter region (Wong et al, 1999) suggests that induction of IkB expression contributes to the ability of the HSR to prevent NFκB activation.…”

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confidence: 99%

Suppressive effects of ansamycins on inducible nitric oxide synthase expression and the development of experimental autoimmune encephalomyelitis

Murphy

Sharp

Shin

et al. 2002

J of Neuroscience Research

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The production of nitric oxide by the inflammatory isoform of nitric oxide synthase (NOS2) in brain glial cells is thought to contribute to the causes and development of neurological diseases and trauma. We previously demonstrated that activation of a heat shock response (HSR) by hyperthermia reduced NOS2 expression in vitro, and in vivo attenuated the clinical and histological symptoms of the demyelinating disease experimental autoimmune encephalomyelitis (EAE; Heneka et al. [2001] J. Neurochem. 77:568-579). Benzoquinoid ansamycins are fungal-derived antibiotics with tyrosine kinase inhibitory properties, and which also induce a HSR by allowing activation of HS transcription factor HSF1. We now show that two members of this class of drugs (geldanamycin and 17-allylamino-17-demethoxygeldanamycin) also induce a HSR in primary rat astrocytes and rat C6 glioma cells. Both drugs dose-dependently reduced nitrite accumulation, NOS2 steady-state mRNA levels, and the cytokine-dependent activation of a rat 2.2-kB NOS2 promoter construct stably expressed in C6 cells. These inhibitory effects were partially reversed by quercetin, a bioflavonoid which prevents HSF1 binding to DNA and thus attenuates the HSR. Ansamycins increased mRNA levels of the inhibitory IkappaBalpha protein, suggesting that inhibition of NFkappaB activation could contribute to their suppressive effects. Finally, in C57BL/6 mice actively immunized to develop EAE, a single injection of geldanamycin at 3 days after immunization reduced disease onset by over 50%. These results indicate that ansamycins can exert potent anti-inflammatory effects on brain glial cells which may provide therapeutic benefit in neuroinflammatory diseases.

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“…1999) and TNF‐α (Snyder et al . 1992; Meng et al . 1999), and the adhesion molecule ICAM1 (Housby et al .…”

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The heat shock response reduces myelin oligodendrocyte glycoprotein‐induced experimental autoimmune encephalomyelitis in mice

Heneka

Sharp

Murphy

et al. 2001

Journal of Neurochemistry

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The stress response (SR) can block in¯ammatory gene expression by preventing activation of transcription factor nuclear factor-kappa B (NF-kB). As in¯ammatory gene expression contributes to the pathogenesis of demyelinating diseases, we tested the effects of the SR on the progression of the demyelinating disease experimental autoimmune encephalomyelitis (EAE). EAE was actively induced in C57BL/6 mice using an encephalitogenic myelin oligodendrocyte glycoprotein (MOG 35255 ) peptide. Whole body hyperthermia was used to induce a heat shock response (HSR) in immunized mice 2 days after the booster MOG 35255 peptide injection. The HSR reduced the incidence of EAE by 70%, delayed disease onset by 6 days, and attenuated disease severity. The HSR attenuated leukocyte in®ltration into CNS assessed by quantitation of perivascular in®ltrates, and by reduced staining for CD4 and CD25 immunopositive T-cells. T-cell activation, assessed by the production of interferon g (IFNg) in response to MOG 35255 , was also decreased by the HSR. The HSR reduced in¯ammatory gene expression in the brain that normally occurs during EAE, including the early increase in RANTES (regulated on activation of normal T-cell expressed and secreted) expression, and the later expression of the inducible form of nitric oxide synthase. The early activation of transcription factor NF-kB was also blocked by the HSR. The ®nding that the SR reduces in¯ammation in the brain and the clinical severity of EAE opens a novel therapeutic approach for prevention of autoimmune diseases. Keywords: cytokines, demyelinating disease, heat shock, in¯ammation, nitric oxide.The stress response (SR) is a protective mechanism elicited by a variety of stimuli, including thermal, chemical, oxidative, graft rejection, and physical trauma, and is thought to confer resistance against subsequent and more lethal stress (Welch 1992). Due to initial studies using hyperthermia to induce the SR, and the reproducibility of using heat as an inducer, the SR is more commonly referred to as the heat shock response (HSR). The HSR causes a general down-regulation of cellular RNA and protein synthesis, and the rapid expression of a speci®c set of proteins termed HS proteins (HSPs) which can protect cells by facilitating re-naturation of denatured proteins and transport to subcellular organelles (Morimoto and Santoro 1998).In addition to protective and chaperoning functions, the HSR also functions in an anti-in¯ammatory mode (Moseley 1998;Santoro 2000). The HSR protects cells from in¯ammatory damage incurred as a consequence of synovitis (Otremski et al. 1994), pulmonary in¯ammation , and endotoxemia (Hotchkiss et al. 1993;Ribeiro et al. 1994). In some cases the HSR was shown to Abbreviations used: EAE, experimental autoimmune encephalomyelitis; HSP, HS protein; HSR, heat shock response; IFNg, interferon g; iNOS, the inducible form of nitric oxide synthase; LPS, lipopolysaccharide; MOG, myelin oligodendrocyte glycoprotein; NF-kB, nuclear factor kappa B; NSAIDs, non-steroidal anti-in¯am...

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HEAT SHOCK PROTEIN 72 SUPPRESSES MACROPHAGE TNFα PRODUCTION BY INHIBITION OF NFB INTRANUCLEAR TRANSLOCATION

Cited by 3 publications

References 0 publications

Hsp70 inhibits lipopolysaccharide‐induced NF‐κB activation by interacting with TRAF6 and inhibiting its ubiquitination

Hsp70 inhibits lipopolysaccharide‐induced NF‐κB activation by interacting with TRAF6 and inhibiting its ubiquitination

Suppressive effects of ansamycins on inducible nitric oxide synthase expression and the development of experimental autoimmune encephalomyelitis

The heat shock response reduces myelin oligodendrocyte glycoprotein‐induced experimental autoimmune encephalomyelitis in mice

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