HSP70 Confers Protection against Indomethacin-Induced Lesions of the Small Intestine

Asano, Teita; Tanaka, Ken Ichiro; Yamakawa, Naoki; Adachi, Hiroaki; Sobue, Gen; Goto, Hidemi; Takeuchi, Koji; Mizushima, Tohru

doi:10.1124/jpet.109.152181

Cited by 40 publications

(34 citation statements)

References 41 publications

(38 reference statements)

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“…On the other hand, TNF-α is the prototypical member of a family of cytokines that also include the Fas, CD40 and TNF-related apoptosis inducing ligands, and that induce apoptosis, differentiation, cell activation, and inflammation (29). Indomethacin-induced epithelial cell apoptosis in vivo was also reported by Takada et al (30) and Asano et al (31). These authors confirmed that apoptotic cell death occurred in the small intestine treated with indomethacin based on an evaluation of caspases-3/7 activity and a TuNeL assay.…”

Section: Discussionmentioning

confidence: 95%

Role of tumor necrosis factor-α in the pathogenesis of indomethacin-induced small intestinal injury in mice

Fukumoto

Naito

Takagi³

et al. 2011

Int J Mol Med

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Abstract. The pathogenesis of small intestinal damage caused by non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin is still unclear. For this reason, there is currently no therapeutic strategy for ameliorating such damage. On the other hand, molecular treatment strategies targeting tumor necrosis factor (TNF)-α exert beneficial effects on intestinal lesions in patients with inflammatory bowel disease (IBD). To clarify the participation of TNF-α in NSAID-induced small intestinal damage, we investigated the effects of indomethacin administration in mice with targeted deletion of the TNF-α gene. Indomethacin (10 mg/kg) was administered subcutaneously to male C57BL/6 (wild-type: WT) mice and TNF-α-deficient (TNF-α -/-) mice to induce small intestinal damage. The ulcer score, the tissue-associated myeloperoxidase (MPO) activity as an index of neutrophil infiltration, and the expression of keratinocyte chemoattractant (KC) mRNA in the small intestinal mucosa were measured. In addition, we performed a TUNEL assay to evaluate indomethacininduced apoptosis of intestinal epithelial cells and measured the expression of caspase-3 protein and Bcl-2 mRNA. The ulcer score, MPO activity, and expression of KC mRNA were significantly increased after indomethacin administration. These increases were significantly inhibited in TNF-α -/-mice compared with WT mice. Apoptotic cells were observed by the TUNEL assay in the area of the ulcerative lesion, and they were significantly fewer in TNF-α -/-mice compared with WT mice. The expression of cleaved caspase-3 protein was induced by indomethacin administration, and significantly inhibited in TNF-α -/-mice compared with that of WT mice. The expression level of Bcl-2 mRNA in indomethacin-treated TNF-α -/-mice was significantly higher than that in WT mice. TNF-α plays an important role in the pathogenesis of indomethacin-induced small intestinal damage. These results suggest that TNF-α could become a new therapeutic target for NSAID-induced small intestinal damage.

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Section: Discussionmentioning

confidence: 95%

Role of tumor necrosis factor-α in the pathogenesis of indomethacin-induced small intestinal injury in mice

Fukumoto

Naito

Takagi³

et al. 2011

Int J Mol Med

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“…As outlined in Introduction, the beneficial effects of HSP70 in animal models of various diseases suggest the potential therapeutic benefit of HSP70 inducers for these conditions (Tanaka et al, 2007Asano et al, 2009;Suemasu et al, 2009;Yamashita et al, 2010), a possibility that can now be expanded to include AD based on the results of the present study. A number of recent studies have revealed new molecules that induce HSPs (Kieran et al, 2004;Westerheide et al, 2004;Yan et al, 2004).…”

Section: Discussionmentioning

confidence: 98%

Suppression of Alzheimer's Disease-Related Phenotypes by Expression of Heat Shock Protein 70 in Mice

Hoshino¹,

Murao²,

Namba³

et al. 2011

J. Neurosci.

151

121

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Amyloid-␤ peptide (A␤) plays an important role in the pathogenesis of Alzheimer's disease (AD). A␤ is generated by proteolysis of ␤-amyloid precursor protein (APP) and is cleared by enzyme-mediated degradation and phagocytosis by microglia and astrocytes. Some cytokines, such as TGF-␤1, stimulate this phagocytosis. In contrast, cellular upregulation of HSP70 expression provides cytoprotection against A␤. HSP70 activity in relation to inhibition of A␤ oligomerization and stimulation of A␤ phagocytosis has also been reported. Although these in vitro results suggest that stimulating the expression of HSP70 could prove effective in the treatment of AD, there is a lack of in vivo evidence supporting this notion. In this study, we address this issue, using transgenic mice expressing HSP70 and/or a mutant form of APP (APPsw). Transgenic mice expressing APPsw showed less of an apparent cognitive deficit when they were crossed with transgenic mice expressing HSP70. Transgenic mice expressing HSP70 also displayed lower levels of A␤, A␤ plaque deposition, and neuronal and synaptic loss than control mice. Immunoblotting experiments and direct measurement of ␤-and ␥-secretase activity suggested that overexpression of HSP70 does not affect the production A␤. In contrast, HSP70 overexpression did lead to upregulation of the expression of A␤-degrading enzyme and TGF-␤1 both in vivo and in vitro. These results suggest that overexpression of HSP70 in mice suppresses not only the pathological but also the functional phenotypes of AD. This study provides the first in vivo evidence confirming the potential therapeutic benefit of HSP70 for the prevention or treatment of AD.

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“…Interestingly, GGA, a leading anti-ulcer drug on the Japanese market, has been reported to be an HSP inducer, up-regulating various HSPs not only in cultured gastric mucosal cells but also in various tissues in vivo (41). It was reported that GGA suppresses not only gastric lesions but also lesions of the small intestine, inflammatory bowel disease-related experimental colitis, and neurodegenerative diseases (39,40,46,47). On the other hand, the use of HSP70 inducers in cosmetics -1) (B).…”

Section: Discussionmentioning

confidence: 99%

Prevention of UVB Radiation-induced Epidermal Damage by Expression of Heat Shock Protein 70

Matsuda

Hoshino

Yamashita

et al. 2010

Journal of Biological Chemistry

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Irradiation with UV light, especially UVB, causes epidermal damage via the induction of apoptosis, inflammatory responses, and DNA damage. Various stressors, including UV light, induce heat shock proteins (HSPs) and the induction, particularly that of HSP70, provides cellular resistance to such stressors. The anti-inflammatory activity of HSP70, such as its inhibition of nuclear factor kappa B (NF-B), was recently revealed. These in vitro results suggest that HSP70 protects against UVB-induced epidermal damage. Here we tested this idea by using transgenic mice expressing HSP70 and cultured keratinocytes. Irradiation of wild-type mice with UVB caused epidermal damage such as induction of apoptosis, which was suppressed in transgenic mice expressing HSP70. UVB-induced apoptosis in cultured keratinocytes was suppressed by overexpression of HSP70. Irradiation of wild-type mice with UVB decreased the cutaneous level of IB-␣ (an inhibitor of NF-B) and increased the infiltration of leukocytes and levels of pro-inflammatory cytokines and chemokines in the epidermis. These inflammatory responses were suppressed in transgenic mice expressing HSP70. In vitro, the overexpression of HSP70 suppressed the expression of pro-inflammatory cytokines and chemokines and increased the level of IB-␣ in keratinocytes irradiated with UVB. UVB induced an increase in cutaneous levels of cyclobutane pyrimidine dimers and 8-hydroxy-2-deoxyguanosine, both of which were suppressed in transgenic mice expressing HSP70. This study provides genetic evidence that HSP70 protects the epidermis from UVB-induced radiation damage. The findings here also suggest that the protective action of HSP70 is mediated by anti-apoptotic, anti-inflammatory, and anti-DNA damage effects.The skin can be structurally classified into several layers, including the most apical layer, the epidermis, containing large numbers of keratinocytes, and a second layer, immediately under this, the dermis, which has a high fibroblast content (1). Skin provides a major interface between the environment and the body and is constantly exposed to an array of physical and chemical stressors. Therefore, in addition to intrinsic causes, harmful exogenous causes are involved in the process of skin damage. Among exogenous harmful agents, UV irradiation is the most relevant to skin damage (photo-damage). UV light can be separated, based on wavelength, into three categories: UVA (320 -400 nm), UVB (290 -320 nm), and UVC (100 -290 nm). Of these, the celldamaging effect of UVA is relatively weak, whereas most UVC is absorbed by the ozone layer (2). Thus, UVB seems to play the central role in photo-damage, such as clinical sunburn, hyperpigmentation, erythema, plaque-like thickening, loss of skin tone, deep furrowing, and fine wrinkle formation, all of which constitute both clinical and cosmetic problems. Furthermore, UVB irradiation induces the development of skin cancer (photo-carcinogenesis) (3). UVB-induced photodamage and photo-carcinogenesis both involve epidermal damage (such as induction...

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HSP70 Confers Protection against Indomethacin-Induced Lesions of the Small Intestine

Cited by 40 publications

References 41 publications

Role of tumor necrosis factor-α in the pathogenesis of indomethacin-induced small intestinal injury in mice

Role of tumor necrosis factor-α in the pathogenesis of indomethacin-induced small intestinal injury in mice

Suppression of Alzheimer's Disease-Related Phenotypes by Expression of Heat Shock Protein 70 in Mice

Prevention of UVB Radiation-induced Epidermal Damage by Expression of Heat Shock Protein 70

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