Regulation of rat heme oxygenase-1 expression by interleukin-6 via the Jak/STAT pathway in hepatocytes

Abteilung Gastroenterologie und Endokrinologie, Uniklinikum, Georg-August-Universität Göttingen, D-37075 Göttingen, Germany.
Journal of Hepatology (Impact Factor: 11.34). 08/2006; 45(1):72-80. DOI: 10.1016/j.jhep.2005.12.019
Source: PubMed


Heme oxygenase-1 (HO-1) can be induced by various stimuli, one of which is interleukin-6 (IL-6). Therefore, the aim of this study was to elucidate the molecular mechanisms responsible for IL-6-dependent HO-1 induction in the liver.
The IL-6-dependent HO-1 regulation in rat primary hepatocytes and HepG2 hepatoma cells was studied by Northern and Western blot analyses, HO-1 promoter reporter gene assays and EMSA.
The HO-1 expression was transcriptionally induced by IL-6 in a time- and dose-dependent manner. Activation of signal transducers and activators of transcription (STAT) factors by the IL-6 receptor was crucial for HO-1 induction. By contrast, negative regulation of HO-1 expression appeared to be mediated through the SH2-domain-containing tyrosine phosphatase-2 (SHP2)/ suppressors of cytokine signaling-3 (SOCS3) binding site within the gp130 IL-6 receptor subunit. Among the three putative STAT binding elements (SBE) in the HO-1 promoter, only the distal one was functional and when deleted, the remaining Luc induction was completely obliterated by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002.
The HO-1 SBE3 mediates HO-1 gene induction by IL-6 mainly via activation of the Jak/STAT pathway.

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Available from: Thomas Kietzmann, Oct 10, 2015
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    • "In contrast, inhibition of IL-10 or HO-1 expression significantly downregulated HO-1 expression and increased TNF-α, IL-1β and IL-6 protein levels. Moreover, the HO-1 expression was transcriptionally induced by IL-6 in a time and dose-dependent manner (Tron et al. 2006). These results suggested a role of HO-1 in the anti-inflammatory effect of IL-10 in gabapentin/morphine-coinjected SNL rats. "
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    ABSTRACT: In the present study, we investigated the anti-inflammatory mechanisms by which gabapentin enhances morphine anti-nociceptive effect in neuropathic pain in rats and the interaction between the anti-nociceptive effects of gabapentin on morphine and the interleukin (IL)-10-heme-oxygenase (HO)-1 signal pathway in a rat model of neuropathic pain. The neuropathic pain model was induced via a left L5/6 spinal nerve ligation (SNL) in rats. The anti-nociceptive effect of gabapentin and IL-10 on morphine was examined over a 7-day period, and the effects of the anti-IL-10 and HO-1 inhibitor zinc protoporphyrin (ZnPP) on gabapentin/morphine co-injection were assessed. Drug administration was given over 7 days, and on day 8, both anti-inflammatory cytokine IL-10, a stress-induced protein HO-1 and pro-inflammatory cytokines IL-1β, IL-6 and TNF-α were measured. Gabapentin attenuated morphine tolerance over 7 days of co-administration, and reduced the expression of pro-inflammatory cytokines but increased IL-10 and HO-1 expression. The effect of gabapentin on morphine was partially blocked using the anti-IL-10 antibody or the HO-1 inhibitor zinc protoporphyrin. Our findings indicated that the anti-nociceptive effects of gabapentin on morphine might be caused by activation of the IL-10-HO-1 signalling pathway, which resulted in the inhibition of the expression of pro-inflammatory cytokines in neuropathic pain in the rat spinal cord.
    Journal of Molecular Neuroscience 02/2014; 54(1). DOI:10.1007/s12031-014-0262-2 · 2.34 Impact Factor
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    • "We again manually searched related literature and further validated the biological relevance of the identified pathway segments. For example, HMOX1 often acts in concert with P450 cytochrome oxidoreductase (encoded by Por) and biliverdin reductase to convert heme into bilirubin, carbon monoxide and iron.25 HMOX1 expression has recently been shown to be regulated by interleukin-6 via the Jak/STAT pathway in hepatocytes.26 "
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    ABSTRACT: A signal transduction pathway (STP) is a cascade composed of a series of signal transferring steps, which often activate one or more transcription factors (TFs) to control the transcription of target genes. Understanding signaling pathways is important to our understanding of the molecular mechanisms of disease. Many condition-annotated pathways have been deposited in public databases. However, condition-annotated pathways are far from complete, considering the large number of possible conditions. Computational methods to assist in the identification of conditionally activated pathways are greatly needed. In this paper, we propose an efficient method to identify conditionally activated pathway segments starting from the identification of conditionally activated TFs, by incorporating protein-DNA binding data, gene expression data and protein interaction data. Applying our methods on several microarray datasets, we have discovered many significantly activated TFs and their corresponding pathway segments, which are supported by evidence in the literature. Availability:
    Bioinformatics and biology insights 11/2009; 3:179-87.
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    • "However, IL- 6 appears to be associated more directly with HO-1 gene activity. An IL-6-responsive element of the human HO-1 gene in liver cells and vascular endothelial cells has been indicated (Mitani et al., 1992; Lavrosky et al., 1996), consistent with subsequent evidence of HO-1 induction by IL-6 in human macrophages (Ricchetti et al., 2004), coronary endothelial cells (Deramaudt et al., 1999), corneal epithelial cells (Neil et al., 1995), and liver cells (Fukuda and Sassa, 1994; Tron et al., 2006), whereas the skin remains untested. The pleiotropic nature of IL-6 is shown by its actions in both proinflammatory and antiinflammatory ways. "
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    ABSTRACT: The proinflammatory cytokine IL-6 is released in the skin following UVB irradiation, but its potential for photoimmune modulation remains unclear. This study utilizes IL-6-deficient mice to demonstrate that IL-6 does not contribute to the normal contact hypersensitivity response, nor to its systemic suppression by UVB radiation or cis-urocanic acid. In contrast, IL-6 was required for the attenuation of UVB- or cis-urocanic acid-induced immunosuppression by sequential or concomitant UVA irradiation. The IL-6 was essential for several reactions previously established to be relevant for UVA photoimmune protection, namely the induction of heme oxygenase-1 (HO-1), the activity of its product carbon monoxide in activating guanylyl cyclase, and the consequent elevation of cutaneous cyclic guanosine monophosphate concentration. In addition, IL-6-deficient mouse skin had an elevated constitutive overexpression of HO activity, apparently not associated with photoimmune protection. This suggested that both the cutaneous level of HO activity, and the receptiveness of the HO-1 gene to stressors like UVA, normally controlled by promoter-binding repressor proteins, may also be under IL-6 control. Thus IL-6 has an important photoimmune protective function through interaction at several levels in the pathway determining the immunologically advantageous actions of UVA radiation. This may constitute a valuable endogenous antiphotocarcinogenic regulatory mechanism.
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