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Heme oxygenase-1 induction attenuates imiquimod-induced psoriasiform inflammation by negative regulation of Stat3 signaling.

Zhang B, Xie S, Su Z, Song S, Xu H, Chen G, Cao W, Yin S, Gao Q, Wang H - Sci Rep (2016)

Bottom Line: Heme oxygenase-1 (HO-1), a stress-inducible protein with a potential anti-inflammatory effect, plays an important role in skin injury and wound healing.In this study, HO-1 activation significantly alleviated the disease-related pathogenesis abnormality.SHP-1-mediated suppression of Stat3 activation after HO-1 activation is a unique molecular mechanism for the regulation of Stat3 activation.

View Article: PubMed Central - PubMed

Affiliation: Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, P.R. China.

ABSTRACT
Heme oxygenase-1 (HO-1), a stress-inducible protein with a potential anti-inflammatory effect, plays an important role in skin injury and wound healing. However, the function of HO-1 in cutaneous inflammatory diseases, such as psoriasis, remains unknown. The abnormal activation of Stat3, a known transcription factor that induces inflammation and regulates cell differentiation, is directly involved in the pathogenesis and development of psoriasis. Hence, targeting Stat3 is potentially beneficial in the treatment of psoriasis. In this study, HO-1 activation significantly alleviated the disease-related pathogenesis abnormality. To determine the mechanism by which HO-1 exerts immune protection on Th17-related cytokines, IL6/IL22-induced Stat3 activation was significantly suppressed, accompanied by decreased cell proliferation and reversed abnormal cell proliferation. Importantly, HO-1-induced Stat3 suppression was mediated through the activation of protein tyrosine phosphatase SHP-1. Overall, our study provides direct evidence indicating that HO-1 might be a useful therapeutic target for psoriasis. SHP-1-mediated suppression of Stat3 activation after HO-1 activation is a unique molecular mechanism for the regulation of Stat3 activation.

No MeSH data available.


Related in: MedlinePlus

Pretreatment of HaCaT cells with HO-1 activators Hemin or CoPP attenuates Th17 cytokine-induced keratinocyte hyperproliferation.(a) HaCaT cells were seeded in 96-cell plates, and stimulated with 10, 25, 50, and 100 ng/mL IL-6 or IL-22 for 24 h before measuring cytokine-induced keratinocyte proliferation using MTS assay, which was based on the cell viability assay. (b) HaCaT cells were seeded in 96-cell plates, and stimulated with 10, 25, 50, and 75 nM Hemin or CoPP for 24 h before measuring cytokine-induced keratinocyte proliferation using MTS assay, which was based on the cell viability assay. (c) HaCaT cells were stimulated with 25 ng/mL IL-6/IL-22 for 24 h in the presence or absence of 25 μM Hemin or CoPP. Total cell numbers were assessed based on the cell viability assay detected using the MTS methods. *represents P < 0.05, which indicates a statistically significant difference. **represents P < 0.005.
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f2: Pretreatment of HaCaT cells with HO-1 activators Hemin or CoPP attenuates Th17 cytokine-induced keratinocyte hyperproliferation.(a) HaCaT cells were seeded in 96-cell plates, and stimulated with 10, 25, 50, and 100 ng/mL IL-6 or IL-22 for 24 h before measuring cytokine-induced keratinocyte proliferation using MTS assay, which was based on the cell viability assay. (b) HaCaT cells were seeded in 96-cell plates, and stimulated with 10, 25, 50, and 75 nM Hemin or CoPP for 24 h before measuring cytokine-induced keratinocyte proliferation using MTS assay, which was based on the cell viability assay. (c) HaCaT cells were stimulated with 25 ng/mL IL-6/IL-22 for 24 h in the presence or absence of 25 μM Hemin or CoPP. Total cell numbers were assessed based on the cell viability assay detected using the MTS methods. *represents P < 0.05, which indicates a statistically significant difference. **represents P < 0.005.

Mentions: HO-1, the rate-limiting enzyme in heme metabolism, performs multiple functions in cytoprotection and immune regulation14. HO-1 expression in the skin was measured to elucidate the effects of HO-1 on psoriasis. Immunochemistry staining showed that psoriatic lesional skin had significantly more HO-1-positive stained cells, and most HO-1-positive stained cells were keratinocytes widely distributed throughout the skin epithelium (Fig. 1c). The influence of HO-1 on keratinocyte growth and differentiation was then examined to address the function of HO-1 in psoriasis. A previous report suggested that the abnormal activation of T cells, especially the Th17 cell subset, contributes to the pathogenesis of psoriasis, and Th17 cell-related cytokines, including IL-17, IL22, and IL-6, are responsible for the altered proliferation and differentiation of keratinocytes and the induction of Stat3 signaling15. To test these effects, HaCaT cells were exposed to various IL-6 and IL-22 doses for 24 h, and cytokine-induced cell proliferation was measured using MTS cell proliferation assay. The results showed that the exposure of HaCaT cells to 10–100 ng/mL IL-6 or IL-22 for 24 h significantly promoted cell proliferation in a dose-dependent manner (Fig. 2a). By contrast, HO-1 activator Hemin or CoPP significantly inhibited HaCaT cell proliferation at the dose of 25 μM (Fig. 2b). HaCaT cells that were simultaneously treated for 24 h with IL-6/IL-22 (25 ng/mL) and HO-1 activators, such as Hemin or CoPP (25 μmol/L), significantly decreased cell proliferation (Fig. 2c). These results suggest that HO-1 activation can block Th17 cytokine-induced cell proliferation in HaCaT cells.


Heme oxygenase-1 induction attenuates imiquimod-induced psoriasiform inflammation by negative regulation of Stat3 signaling.

Zhang B, Xie S, Su Z, Song S, Xu H, Chen G, Cao W, Yin S, Gao Q, Wang H - Sci Rep (2016)

Pretreatment of HaCaT cells with HO-1 activators Hemin or CoPP attenuates Th17 cytokine-induced keratinocyte hyperproliferation.(a) HaCaT cells were seeded in 96-cell plates, and stimulated with 10, 25, 50, and 100 ng/mL IL-6 or IL-22 for 24 h before measuring cytokine-induced keratinocyte proliferation using MTS assay, which was based on the cell viability assay. (b) HaCaT cells were seeded in 96-cell plates, and stimulated with 10, 25, 50, and 75 nM Hemin or CoPP for 24 h before measuring cytokine-induced keratinocyte proliferation using MTS assay, which was based on the cell viability assay. (c) HaCaT cells were stimulated with 25 ng/mL IL-6/IL-22 for 24 h in the presence or absence of 25 μM Hemin or CoPP. Total cell numbers were assessed based on the cell viability assay detected using the MTS methods. *represents P < 0.05, which indicates a statistically significant difference. **represents P < 0.005.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4759695&req=5

f2: Pretreatment of HaCaT cells with HO-1 activators Hemin or CoPP attenuates Th17 cytokine-induced keratinocyte hyperproliferation.(a) HaCaT cells were seeded in 96-cell plates, and stimulated with 10, 25, 50, and 100 ng/mL IL-6 or IL-22 for 24 h before measuring cytokine-induced keratinocyte proliferation using MTS assay, which was based on the cell viability assay. (b) HaCaT cells were seeded in 96-cell plates, and stimulated with 10, 25, 50, and 75 nM Hemin or CoPP for 24 h before measuring cytokine-induced keratinocyte proliferation using MTS assay, which was based on the cell viability assay. (c) HaCaT cells were stimulated with 25 ng/mL IL-6/IL-22 for 24 h in the presence or absence of 25 μM Hemin or CoPP. Total cell numbers were assessed based on the cell viability assay detected using the MTS methods. *represents P < 0.05, which indicates a statistically significant difference. **represents P < 0.005.
Mentions: HO-1, the rate-limiting enzyme in heme metabolism, performs multiple functions in cytoprotection and immune regulation14. HO-1 expression in the skin was measured to elucidate the effects of HO-1 on psoriasis. Immunochemistry staining showed that psoriatic lesional skin had significantly more HO-1-positive stained cells, and most HO-1-positive stained cells were keratinocytes widely distributed throughout the skin epithelium (Fig. 1c). The influence of HO-1 on keratinocyte growth and differentiation was then examined to address the function of HO-1 in psoriasis. A previous report suggested that the abnormal activation of T cells, especially the Th17 cell subset, contributes to the pathogenesis of psoriasis, and Th17 cell-related cytokines, including IL-17, IL22, and IL-6, are responsible for the altered proliferation and differentiation of keratinocytes and the induction of Stat3 signaling15. To test these effects, HaCaT cells were exposed to various IL-6 and IL-22 doses for 24 h, and cytokine-induced cell proliferation was measured using MTS cell proliferation assay. The results showed that the exposure of HaCaT cells to 10–100 ng/mL IL-6 or IL-22 for 24 h significantly promoted cell proliferation in a dose-dependent manner (Fig. 2a). By contrast, HO-1 activator Hemin or CoPP significantly inhibited HaCaT cell proliferation at the dose of 25 μM (Fig. 2b). HaCaT cells that were simultaneously treated for 24 h with IL-6/IL-22 (25 ng/mL) and HO-1 activators, such as Hemin or CoPP (25 μmol/L), significantly decreased cell proliferation (Fig. 2c). These results suggest that HO-1 activation can block Th17 cytokine-induced cell proliferation in HaCaT cells.

Bottom Line: Heme oxygenase-1 (HO-1), a stress-inducible protein with a potential anti-inflammatory effect, plays an important role in skin injury and wound healing.In this study, HO-1 activation significantly alleviated the disease-related pathogenesis abnormality.SHP-1-mediated suppression of Stat3 activation after HO-1 activation is a unique molecular mechanism for the regulation of Stat3 activation.

View Article: PubMed Central - PubMed

Affiliation: Center for Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, P.R. China.

ABSTRACT
Heme oxygenase-1 (HO-1), a stress-inducible protein with a potential anti-inflammatory effect, plays an important role in skin injury and wound healing. However, the function of HO-1 in cutaneous inflammatory diseases, such as psoriasis, remains unknown. The abnormal activation of Stat3, a known transcription factor that induces inflammation and regulates cell differentiation, is directly involved in the pathogenesis and development of psoriasis. Hence, targeting Stat3 is potentially beneficial in the treatment of psoriasis. In this study, HO-1 activation significantly alleviated the disease-related pathogenesis abnormality. To determine the mechanism by which HO-1 exerts immune protection on Th17-related cytokines, IL6/IL22-induced Stat3 activation was significantly suppressed, accompanied by decreased cell proliferation and reversed abnormal cell proliferation. Importantly, HO-1-induced Stat3 suppression was mediated through the activation of protein tyrosine phosphatase SHP-1. Overall, our study provides direct evidence indicating that HO-1 might be a useful therapeutic target for psoriasis. SHP-1-mediated suppression of Stat3 activation after HO-1 activation is a unique molecular mechanism for the regulation of Stat3 activation.

No MeSH data available.


Related in: MedlinePlus