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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

High levels of Stat3 activation and increased HO-1 expression are preferentially associated with abnormal keratinocyte differentiation and overproliferation in psoriatic lesional skin.Formalin-fixed paraffin-embedded tissue sections from psoriasis patients and healthy individuals were examined by histopathological assay. (a) H&E staining of normal skin and psoriatic lesional skin. (b) Representative IHC staining for PY-Stat3 (Tyr705), Ki67, keratin 16, or keratin 17 Abs in serial sections of psoriatic lesional skin or healthy controls. (c) The statistical analysis of IHC staining for PY-Stat3 (Tyr705), Ki67, keratin 16, or keratin 17 in psoriatic lesional skin or healthy controls. (d) Representative IHC staining for HO-1 or SHP-1 in serial sections of psoriatic lesional skin or healthy controls. (e) The statistical analysis of IHC staining for HO-1 or SHP-1 in serial sections of psoriatic lesional skin or healthy controls. Magnification: ×100. *represents P < 0.05, which indicates a statistically significant difference.
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f1: High levels of Stat3 activation and increased HO-1 expression are preferentially associated with abnormal keratinocyte differentiation and overproliferation in psoriatic lesional skin.Formalin-fixed paraffin-embedded tissue sections from psoriasis patients and healthy individuals were examined by histopathological assay. (a) H&E staining of normal skin and psoriatic lesional skin. (b) Representative IHC staining for PY-Stat3 (Tyr705), Ki67, keratin 16, or keratin 17 Abs in serial sections of psoriatic lesional skin or healthy controls. (c) The statistical analysis of IHC staining for PY-Stat3 (Tyr705), Ki67, keratin 16, or keratin 17 in psoriatic lesional skin or healthy controls. (d) Representative IHC staining for HO-1 or SHP-1 in serial sections of psoriatic lesional skin or healthy controls. (e) The statistical analysis of IHC staining for HO-1 or SHP-1 in serial sections of psoriatic lesional skin or healthy controls. Magnification: ×100. *represents P < 0.05, which indicates a statistically significant difference.

Mentions: Skin inflammation is among the major features of psoriasis. The pathological features of psoriasis were initially characterized by immunohistochemical staining12. In accordance with previous studies, H&E staining showed that psoriatic lesional skin exhibited severe and significant epidermal thickening and parakeratosis, accompanied by increased lymphocyte infiltration (Fig. 1a). The expression patterns of several crucial molecules, including Ki67, keratin 16, and keratin 17, were analyzed to further investigate the molecular pathological features. Figure 1b shows significantly increased expression of Ki67, a key protein marker associated with cell proliferation. Tissue distribution analysis showed that Ki67-positive stained cells in normal skin were located mainly in the basal/germinal layer of the skin, whereas Ki67-positive stained cells in psoriatic lesional skin were widely distributed, covering the entire skin epidermal layer. These results indicate that the keratinocytes from psoriatic patients underwent enhanced cell proliferation. The expression levels of keratin family proteins, such as keratin 16 and keratin 17, which are markers for hyperproliferation and abnormal differentiation in keratinocytes13, also significantly increased.


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)

High levels of Stat3 activation and increased HO-1 expression are preferentially associated with abnormal keratinocyte differentiation and overproliferation in psoriatic lesional skin.Formalin-fixed paraffin-embedded tissue sections from psoriasis patients and healthy individuals were examined by histopathological assay. (a) H&E staining of normal skin and psoriatic lesional skin. (b) Representative IHC staining for PY-Stat3 (Tyr705), Ki67, keratin 16, or keratin 17 Abs in serial sections of psoriatic lesional skin or healthy controls. (c) The statistical analysis of IHC staining for PY-Stat3 (Tyr705), Ki67, keratin 16, or keratin 17 in psoriatic lesional skin or healthy controls. (d) Representative IHC staining for HO-1 or SHP-1 in serial sections of psoriatic lesional skin or healthy controls. (e) The statistical analysis of IHC staining for HO-1 or SHP-1 in serial sections of psoriatic lesional skin or healthy controls. Magnification: ×100. *represents P < 0.05, which indicates a statistically significant difference.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: High levels of Stat3 activation and increased HO-1 expression are preferentially associated with abnormal keratinocyte differentiation and overproliferation in psoriatic lesional skin.Formalin-fixed paraffin-embedded tissue sections from psoriasis patients and healthy individuals were examined by histopathological assay. (a) H&E staining of normal skin and psoriatic lesional skin. (b) Representative IHC staining for PY-Stat3 (Tyr705), Ki67, keratin 16, or keratin 17 Abs in serial sections of psoriatic lesional skin or healthy controls. (c) The statistical analysis of IHC staining for PY-Stat3 (Tyr705), Ki67, keratin 16, or keratin 17 in psoriatic lesional skin or healthy controls. (d) Representative IHC staining for HO-1 or SHP-1 in serial sections of psoriatic lesional skin or healthy controls. (e) The statistical analysis of IHC staining for HO-1 or SHP-1 in serial sections of psoriatic lesional skin or healthy controls. Magnification: ×100. *represents P < 0.05, which indicates a statistically significant difference.
Mentions: Skin inflammation is among the major features of psoriasis. The pathological features of psoriasis were initially characterized by immunohistochemical staining12. In accordance with previous studies, H&E staining showed that psoriatic lesional skin exhibited severe and significant epidermal thickening and parakeratosis, accompanied by increased lymphocyte infiltration (Fig. 1a). The expression patterns of several crucial molecules, including Ki67, keratin 16, and keratin 17, were analyzed to further investigate the molecular pathological features. Figure 1b shows significantly increased expression of Ki67, a key protein marker associated with cell proliferation. Tissue distribution analysis showed that Ki67-positive stained cells in normal skin were located mainly in the basal/germinal layer of the skin, whereas Ki67-positive stained cells in psoriatic lesional skin were widely distributed, covering the entire skin epidermal layer. These results indicate that the keratinocytes from psoriatic patients underwent enhanced cell proliferation. The expression levels of keratin family proteins, such as keratin 16 and keratin 17, which are markers for hyperproliferation and abnormal differentiation in keratinocytes13, also significantly increased.

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