Adiponectin and Heme Oxygenase-1 Suppress TLR4/MyD88-Independent Signaling in Rat Kupffer Cells and in Mice after Chronic Ethanol Exposure

Title
Adiponectin and Heme Oxygenase-1 Suppress TLR4/MyD88-Independent Signaling in Rat Kupffer Cells and in Mice after Chronic Ethanol Exposure
Author(s)
Palash Mandal[Palash Mandal]Sanjoy Roychowdhury [Sanjoy Roychowdhury ]박필훈Brian T Pratt[Brian T Pratt]Thierry Roger[Thierry Roger]Laura E Nagy[Laura E Nagy]
Keywords
ALCOHOLIC LIVER-DISEASE; TNF-ALPHA PRODUCTION; GENE-EXPRESSION; FATTY LIVER; INJURY; RECEPTORS; INFLAMMATION; INHIBITION; ACTIVATION; STEATOSIS
Issue Date
201010
Publisher
AMER ASSOC IMMUNOLOGISTS
Citation
JOURNAL OF IMMUNOLOGY, v.185, no.8, pp.4928 - 4937
Abstract
Alcoholic liver disease is mediated via activation of TLR4 signaling; MyD88-dependent and -independent signals are important contributors to injury in mouse models. Adiponectin, an anti-inflammatory adipokine, suppresses TLR4/MyD88-dependent responses via induction of heme oxygenase-1 (HO-1). Here we investigated the interactions between chronic ethanol, adiponectin, and HO-1 in regulation of TLR4/MyD88-independent signaling in macrophages and an in vivo mouse model. After chronic ethanol feeding, LPS-stimulated expression of IFN-beta and CXCL10 mRNA was increased in primary cultures of Kupffer cells compared with pair-fed control mice. Treatment of Kupffer cells with globular adiponectin (gAcrp) normalized this response. LPS-stimulated IFN-beta/CXCL10 mRNA and CXCL10 protein was also reduced in RAW 264.7 macrophages treated with gAcrp or full-length adiponectin. gAcrp and full-length adiponectin acted via adiponectin receptors 1 and 2, respectively. gAcrp decreased TLR4 expression in both Kupffer cells and RAW 264.7 macrophages. Small interfering RNA knockdown of HO-1 or inhibition of HO-1 activity with zinc protoporphyrin blocked these effects of gAcrp. C57BL/6 mice were exposed to chronic ethanol feeding, with or without treatment with cobalt protoporphyrin, to induce HO-1. After chronic ethanol feeding, mice were sensitized to in vivo challenge with LPS, expressing increased IFN-beta/CXCL10 mRNA and CXCL10 protein in liver compared with control mice. Pretreatment with cobalt protoporphyrin 24 h before LPS challenge normalized this effect of ethanol. Adiponectin and induction of HO-1 potently suppressed TLR4-dependent/MyD88-independent cytokine expression in primary Kupffer cells from rats and in mouse liver after chronic ethanol exposure. These data suggest that induction of HO-1 may be a useful therapeutic strategy in alcoholic liver disease. The Journal of Immunology, 2010, 185: 4928-4937.
URI
http://hdl.handle.net/YU.REPOSITORY/23488http://dx.doi.org/10.4049/jimmunol.1002060
ISSN
0022-1767
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약학대학 > 약학부 > Articles
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