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CTRP9 Regulates Growth, Differentiation, and Apoptosis in Human Keratinocytes through TGF?1-p38-Dependent Pathway.

ABSTRACT: Impairment of wound healing is a common problem in individuals with diabetes. Adiponectin, an adipocyte-derived cytokine, has many beneficial effects on metabolic disorders such as diabetes, obesity, hypertension, and dyslipidemia. C1q/TNF-Related Protein 9 (CTRP9), the closest paralog of adiponectin, has been reported to have beneficial effects on wound healing. In the current study, we demonstrate that CTRP9 regulates growth, differentiation, and apoptosis of HaCaT human keratinocytes. We found that CTRP9 augmented expression of transforming growth factor beta 1 (TGF?1) by transcription factor activator protein 1 (AP-1) binding activity and phosphorylation of p38 in a dose-dependent manner. Furthermore, siRNA-mediated suppression of TGF?1 reversed the increase in p38 phosphorylation induced by CTRP9. siRNA-mediated suppression of TGF?1 or p38 significantly abrogated the effects of CTRP9 on cell proliferation and differentiation while inducing apoptosis, implying that CTRP9 stimulates wound recovery through a TGF?1-dependent pathway in keratinocytes. Furthermore, intravenous injection of CTRP9 via tail vein suppressed mRNA expression of Ki67 and involucrin whereas it augmented TGF?1 mRNA expression and caspase 3 activity in skin of type 1 diabetes animal models. In conclusion, our results suggest that CTRP9 has suppressive effects on hyperkeratosis, providing a potentially effective therapeutic strategy for diabetic wounds.

SUBMITTER: Jung TW

PROVIDER: S-EPMC5750709 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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CTRP9 Regulates Growth, Differentiation, and Apoptosis in Human Keratinocytes through TGFβ1-p38-Dependent Pathway.

Jung Tae Woo TW Park Hyung Sub HS Choi Geum Hee GH Kim Daehwan D Lee Taeseung T

Molecules and cells 20171116 12

Impairment of wound healing is a common problem in individuals with diabetes. Adiponectin, an adipocyte-derived cytokine, has many beneficial effects on metabolic disorders such as diabetes, obesity, hypertension, and dyslipidemia. C1q/TNF-Related Protein 9 (CTRP9), the closest paralog of adiponectin, has been reported to have beneficial effects on wound healing. In the current study, we demonstrate that CTRP9 regulates growth, differentiation, and apoptosis of HaCaT human keratinocytes. We foun ...[more]

PMID: 29145717

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Project description:The transforming growth factor-beta 1 (TGF?1) and NF?B pathways are important regulators of epidermal homeostasis, inflammatory responses and carcinogenesis. Previous studies have shown extensive crosstalk between these pathways that is cell type and context dependent, but this has not been well-characterized in epidermal keratinocytes. Here we show that in primary mouse keratinocytes, TGF?1 induces NF?B-luciferase reporter activity that is dependent on both NF?B and Smad3. TGF?1-induced NF?B-luciferase activity was blocked by the I?B inhibitor parthenolide, the I?B super-repressor, a dominant negative TGF?1-activated kinase 1 (TAK1) and genetic deletion of NF?B1. Coexpression of NF?B p50 or p65 subunits enhanced NF?B-luciferase activity. Similarly, inhibition of the TGF?1 type I receptor with SB431542 or genetic deletion of Smad3 blocked TGF?1 induction of NF?B-luciferase. TGF?1 rapidly induced IKK phosphorylation but did not cause a detectable decrease in cytoplasmic I?B levels or nuclear translocation of NF?B subunits, although EMSA showed rapid NF?B nuclear binding activity that could be blocked by SB431542 treatment. TNF?, a well characterized NF?B target gene was also induced by TGF?1 and this was blocked in NF?B+/- and -/- keratinocytes and by the I?B super-repressor. To test the effects of the TGF?1 pathway on a biologically relevant activator of NF?B, we exposed mice and primary keratinocytes in culture to UVB irradiation. In primary keratinocytes UVB caused a detectable increase in levels of Smad2 phosphorylation that was dependent on ALK5, but no significant increase in SBE-dependent gene expression. Inhibition of TGF?1 signaling in primary keratinocytes with SB431542 or genetic deletion of Tgfb1 or Smad3 suppressed UVB induction of TNF? message. Similarly, UVB induction of TNF? mRNA was blocked in skin of Tgfb1+/- mice. These studies demonstrate that intact TGF?1 signaling is required for NF?B-dependent gene expression in mouse keratinocytes and skin and suggest that a convergence of these pathways in the nucleus rather than the cytoplasm may be critical for regulation of inflammatory pathways in skin by TGF?1.

Dataset Information

CTRP9 Regulates Growth, Differentiation, and Apoptosis in Human Keratinocytes through TGF?1-p38-Dependent Pathway.

Publications

CTRP9 Regulates Growth, Differentiation, and Apoptosis in Human Keratinocytes through TGFβ1-p38-Dependent Pathway.

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