Molecules and Cells

  • 제40권12호
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  • Pages.906-915
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  • 2017
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  • 1016-8478(pISSN)
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  • 0219-1032(eISSN)
한국분자세포생물학회 (Korean Society for Molecular and Cellular Biology)
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CTRP9 Regulates Growth, Differentiation, and Apoptosis in Human Keratinocytes through TGFβ1-p38-Dependent Pathway

  • Jung, Tae Woo (Research Administration Team, Seoul National University Bundang Hospital) ;
  • Park, Hyung Sub (Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine) ;
  • Choi, Geum Hee (Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine) ;
  • Kim, Daehwan (Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine) ;
  • Lee, Taeseung (Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine)
  • 투고 : 2017.06.15
  • 심사 : 2017.11.05
  • 발행 : 2017.12.31
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초록

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 ($TGF{\beta}1$) by transcription factor activator protein 1 (AP-1) binding activity and phosphorylation of p38 in a dose-dependent manner. Furthermore, siRNA-mediated suppression of $TGF{\beta}1$ reversed the increase in p38 phosphorylation induced by CTRP9. siRNA-mediated suppression of $TGF{\beta}1$ or p38 significantly abrogated the effects of CTRP9 on cell proliferation and differentiation while inducing apoptosis, implying that CTRP9 stimulates wound recovery through a $TGF{\beta}1$-dependent pathway in keratinocytes. Furthermore, intravenous injection of CTRP9 via tail vein suppressed mRNA expression of Ki67 and involucrin whereas it augmented $TGF{\beta}1$ 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.

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참고문헌

  1. Arita, Y., Kihara, S., Ouchi, N., Maeda, K., Kuriyama, H., Okamoto, Y., Kumada, M., Hotta, K., Nishida, M., Takahashi, M., et al. (2002). Adipocyte-derived plasma protein adiponectin acts as a plateletderived growth factor-BB-binding protein and regulates growth factor-induced common postreceptor signal in vascular smooth muscle cell. Circulation 105, 2893-2898. https://doi.org/10.1161/01.CIR.0000018622.84402.FF
  2. Bandyopadhyay, B., Fan, J., Guan, S., Li, Y., Chen, M., Woodley, D.T., and Li, W. (2006). A "traffic control" role for TGFbeta3: orchestrating dermal and epidermal cell motility during wound healing. J. Cell Biol. 172, 1093-1105. https://doi.org/10.1083/jcb.200507111
  3. Bierie, B., and Moses, H.L. (2006). Tumour microenvironment: TGFbeta: the molecular Jekyll and Hyde of cancer. Nat. Rev. Cancer 6, 506-520. https://doi.org/10.1038/nrc1926
  4. Blakytny, R., and Jude, E. (2006) The molecular biology of chronic wounds and delayed healing in diabetes. Diabet. Med. 23, 594-608. https://doi.org/10.1111/j.1464-5491.2006.01773.x
  5. Deyrieux, A.F., and Wilson, V.G. (2007). In vitro culture conditions to study keratinocyte differentiation using the HaCaT cell line. Cytotechnology 54, 77-83. https://doi.org/10.1007/s10616-007-9076-1
  6. Efimova, T., LaCelle, P., Welter, J.F., and Eckert, R.L. (1998). Regulation of human involucrin promoter activity by a protein kinase C, Ras, MEKK1, MEK3, p38/RK, AP1 signal transduction pathway. J. Biol. Chem. 273, 24387-24395. https://doi.org/10.1074/jbc.273.38.24387
  7. Ferrari, G., Terushkin, V., Wolff, M.J., Zhang, X., Valacca, C., Poggio, P., Pintucci, G., and Mignatti, P. (2012). TGF-beta1 induces endothelial cell apoptosis by shifting VEGF activation of p38(MAPK) from the prosurvival p38beta to proapoptotic p38alpha. Mol. Cancer Res. 10, 605-614. https://doi.org/10.1158/1541-7786.MCR-11-0507
  8. Frank, S., Madlener, M., and Werner, S. (1996). Transforming growth factors beta1, beta2, and beta3 and their receptors are differentially regulated during normal and impaired wound healing. J. Biol. Chem. 271, 10188-10193. https://doi.org/10.1074/jbc.271.17.10188
  9. Gault, N., Vozenin-Brotons, M.C., Calenda, A., Lefaix, J.L., and Martin, M.T. (2002). Promoter sequences involved in transforming growth factor beta1 gene induction in HaCaT keratinocytes after gamma irradiation. Radiation Res. 157, 249-255. https://doi.org/10.1667/0033-7587(2002)157[0249:PSIITG]2.0.CO;2
  10. Hwang, Y.C., Woo Oh, S., Park, S.W., and Park, C.Y. (2014). Association of serum C1q/TNF-Related Protein-9 (CTRP9) concentration with visceral adiposity and metabolic syndrome in humans. Int. J. Obesity 38, 1207-1212. https://doi.org/10.1038/ijo.2013.242
  11. Iwasaki, Y., Nishiyama, M., Taguchi, T., Kambayashi, M., Asai, M., Yoshida, M., Nigawara, T., and Hashimoto, K. (2007). Activation of AMP-activated protein kinase stimulates proopiomelanocortin gene transcription in AtT20 corticotroph cells. Am. J. Physiol. Endocrinol. Metabol. 292, E1899-1905. https://doi.org/10.1152/ajpendo.00116.2006
  12. Jee, S.H., Ahn, C.W., Park, J.S., Park, C.G., Kim, H.S., Lee, S.H., Park, S., Lee, M., Lee, C.B., Park, H.S., et al. (2013). Serum adiponectin and type 2 diabetes: a 6-year follow-up cohort study. Diabetes Metabol. J. 37, 252-261. https://doi.org/10.4093/dmj.2013.37.4.252
  13. Jin, X., Ren, S., Macarak, E., and Rosenbloom, J. (2016). Pathobiological mechanisms of peritoneal adhesions: The mesenchymal transition of rat peritoneal mesothelial cells induced by TGF-beta1 and IL-6 requires activation of Erk1/2 and Smad2 linker region phosphorylation. Matrix Biol. 51, 55-64. https://doi.org/10.1016/j.matbio.2016.01.017
  14. Jung, C.H., Lee, M.J., Kang, Y.M., Jang, J.E., Leem, J., Lee, Y.L., Seol, S.M., Yoon, H.K., Lee, W.J., and Park, J.Y. (2014). Association of serum C1q/TNF-related protein-9 concentration with arterial stiffness in subjects with type 2 diabetes. J. Clin. Endocrinol. Metabol. 99, E2477-2484. https://doi.org/10.1210/jc.2014-2524
  15. Jung, T.W., Hong, H.C., Hwang, H.J., Yoo, H.J., Baik, S.H., and Choi, K.M. (2015). C1q/TNF-Related Protein 9 (CTRP9) attenuates hepatic steatosis via the autophagy-mediated inhibition of endoplasmic reticulum stress. Mol. Cell. Endocrinol. 417, 131-140. https://doi.org/10.1016/j.mce.2015.09.027
  16. Kambara, T., Ohashi, K., Shibata, R., Ogura, Y., Maruyama, S., Enomoto, T., Uemura, Y., Shimizu, Y., Yuasa, D., Matsuo, K., et al. (2012). CTRP9 protein protects against myocardial injury following ischemia-reperfusion through AMP-activated protein kinase (AMPK)-dependent mechanism. J. Biol. Chem. 287, 18965-18973. https://doi.org/10.1074/jbc.M112.357939
  17. Kang, H.J., Soh, Y., Kim, M.S., Lee, E.J., Surh, Y.J., Kim, H.R., Kim, S.H., and Moon, A. (2003). Roles of JNK-1 and p38 in selective induction of apoptosis by capsaicin in ras-transformed human breast epithelial cells. Int. J. Cancer 103, 475-482. https://doi.org/10.1002/ijc.10855
  18. Kawai, K., Kageyama, A., Tsumano, T., Nishimoto, S., Fukuda, K., Yokoyama, S., Oguma, T., Fujita, K., Yoshimoto, S., Yanai, A., et al. (2008). Effects of adiponectin on growth and differentiation of human keratinocytes--implication of impaired wound healing in diabetes. Biochem. Biophys. Res. Commun. 374, 269-273. https://doi.org/10.1016/j.bbrc.2008.07.045
  19. Khalil, N. (1999). TGF-beta: from latent to active. Microb. Infect. 1, 1255-1263. https://doi.org/10.1016/S1286-4579(99)00259-2
  20. Kim, S.J., Glick, A., Sporn, M.B., and Roberts, A.B. (1989). Characterization of the promoter region of the human transforming growth factor-beta 1 gene. J. Biol. Chem. 264, 402-408.
  21. Koch, R.M., Roche, N.S., Parks, W.T., Ashcroft, G.S., Letterio, J.J., and Roberts, A.B. (2000). Incisional wound healing in transforming growth factor-beta1 null mice. Wound Repair Regener. 8, 179-191. https://doi.org/10.1046/j.1524-475x.2000.00179.x
  22. Kyriakis, J.M., and Avruch, J. (2001). Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol. Rev. 81, 807-869. https://doi.org/10.1152/physrev.2001.81.2.807
  23. Liu, Q., Zhang, Y., Mao, H., Chen, W., Luo, N., Zhou, Q., Chen, W., and Yu, X. (2012). A crosstalk between the Smad and JNK signaling in the TGF-beta-induced epithelial-mesenchymal transition in rat peritoneal mesothelial cells. PloS one 7, e32009. https://doi.org/10.1371/journal.pone.0032009
  24. Maas-Szabowski, N., Starker, A., and Fusenig, N.E. (2003). Epidermal tissue regeneration and stromal interaction in HaCaT cells is initiated by TGF-alpha. J. Cell Sci. 116, 2937-2948. https://doi.org/10.1242/jcs.00474
  25. Massague, J., Blain, S.W., and Lo, R.S. (2000) TGFbeta signaling in growth control, cancer, and heritable disorders. Cell 103, 295-309. https://doi.org/10.1016/S0092-8674(00)00121-5
  26. Matsuda, M., Shimomura, I., Sata, M., Arita, Y., Nishida, M., Maeda, N., Kumada, M., Okamoto, Y., Nagaretani, H., Nishizawa, H., et al. (2002) Role of adiponectin in preventing vascular stenosis. The missing link of adipo-vascular axis. J. Biol. Chem. 277, 37487-37491. https://doi.org/10.1074/jbc.M206083200
  27. Nebreda, A.R., and Porras, A. (2000). p38 MAP kinases: beyond the stress response. Trends Biochem. Sci. 25, 257-260. https://doi.org/10.1016/S0968-0004(00)01595-4
  28. O'Kane, S., and Ferguson, M.W. (1997) Transforming growth factor beta s and wound healing. Int. J . Biochem. Cell Biol. 29, 63-78. https://doi.org/10.1016/S1357-2725(96)00120-3
  29. Pavlinkova, G., Salbaum, J.M., and Kappen, C. (2008). Wnt signaling in caudal dysgenesis and diabetic embryopathy. Birth Defects Res. A Clin. Mol. Teratol. 82, 710-719. https://doi.org/10.1002/bdra.20495
  30. Peterson, J.M., Wei, Z., Seldin, M.M., Byerly, M.S., Aja, S., and Wong, G.W. (2013). CTRP9 transgenic mice are protected from dietinduced obesity and metabolic dysfunction. Am. J. Physiol. Regul. Integr. Comp. Physiol. 305, R522-533. https://doi.org/10.1152/ajpregu.00110.2013
  31. Presser, L.D., McRae, S., and Waris, G. (2013). Activation of TGFbeta1 promoter by hepatitis C virus-induced AP-1 and Sp1: role of TGF-beta1 in hepatic stellate cell activation and invasion. PloS one 8, e56367. https://doi.org/10.1371/journal.pone.0056367
  32. Saika, S., Okada, Y., Miyamoto, T., Yamanaka, O., Ohnishi, Y., Ooshima, A., Liu, C.Y., Weng, D., and Kao, W.W. (2004). Role of p38 MAP kinase in regulation of cell migration and proliferation in healing corneal epithelium. Invest. Ophthalmol. Vis. Sci. 45, 100-109. https://doi.org/10.1167/iovs.03-0700
  33. Seldin, M.M., Tan, S.Y., and Wong, G.W. (2014). Metabolic function of the CTRP family of hormones. Rev. Endocrine Metabol. Disord. 15, 111-123. https://doi.org/10.1007/s11154-013-9255-7
  34. Singer, A.J., and Clark, R.A. (1999). Cutaneous wound healing. New England J. Med. 341, 738-746. https://doi.org/10.1056/NEJM199909023411006
  35. Sun, Y., Pi, J., Wang, X., Tokar, E.J., Liu, J., and Waalkes, M.P. (2009). Aberrant cytokeratin expression during arsenic-induced acquired malignant phenotype in human HaCaT keratinocytes consistent with epidermal carcinogenesis. Toxicology 262, 162-170. https://doi.org/10.1016/j.tox.2009.06.003
  36. Takekawa, M., Tatebayashi, K., Itoh, F., Adachi, M., Imai, K., and Saito, H. (2002). Smad-dependent GADD45beta expression mediates delayed activation of p38 MAP kinase by TGF-beta. EMBO J. 21, 6473-6482. https://doi.org/10.1093/emboj/cdf643
  37. Takemura, Y., Ouchi, N., Shibata, R., Aprahamian, T., Kirber, M.T., Summer, R.S., Kihara, S., and Walsh, K. (2007). Adiponectin modulates inflammatory reactions via calreticulin receptor-dependent clearance of early apoptotic bodies. J. Clin. Invest. 117, 375-386. https://doi.org/10.1172/JCI29709
  38. Uemura, Y., Shibata, R., Ohashi, K., Enomoto, T., Kambara, T., Yamamoto, T., Ogura, Y., Yuasa, D., Joki, Y., Matsuo, K., et al. (2013). Adipose-derived factor CTRP9 attenuates vascular smooth muscle cell proliferation and neointimal formation. FASEB J. 27, 25-33. https://doi.org/10.1096/fj.12-213744
  39. Usui, M.L., Mansbridge, J.N., Carter, W.G., Fujita, M., and Olerud, J.E. (2008). Keratinocyte migration, proliferation, and differentiation in chronic ulcers from patients with diabetes and normal wounds. J. Histochem. Cytochem. 56, 687-696. https://doi.org/10.1369/jhc.2008.951194
  40. Wang, Y., Lam, K.S., Xu, J.Y., Lu, G., Xu, L.Y., Cooper, G.J., and Xu, A. (2005). Adiponectin inhibits cell proliferation by interacting with several growth factors in an oligomerization-dependent manner. J. Biol. Chem. 280, 18341-18347. https://doi.org/10.1074/jbc.M501149200
  41. Wang, X.J., Han, G., Owens, P., Siddiqui, Y., and Li, A.G. (2006). Role of TGF beta-mediated inflammation in cutaneous wound healing. J. Invest. Dermatol. 11, 112-117. https://doi.org/10.1038/sj.jidsymp.5650004
  42. Wang, W., Lau, W.B., Wang, Y., Ma, X., and Li, R. (2016). Reduction of CTRP9, a novel anti-platelet adipokine, contributes to abnormal platelet activity in diabetic animals. Cardiovasc. Diabetol. 15, 6. https://doi.org/10.1186/s12933-015-0321-1
  43. Wei, L., Liu, Y., Kaneto, H., and Fanburg, B.L. (2010). JNK regulates serotonin-mediated proliferation and migration of pulmonary artery smooth muscle cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 298, L863-869. https://doi.org/10.1152/ajplung.00281.2009
  44. Wei, Z., Lei, X., Petersen, P.S., Aja, S., and Wong, G.W. (2014). Targeted deletion of C1q/TNF-related protein 9 increases food intake, decreases insulin sensitivity, and promotes hepatic steatosis in mice. American journal of physiology. Endocrinol. Metabol. 306, E779-790.
  45. Whitehead, J.P., Richards, A.A., Hickman, I.J., Macdonald, G.A., and Prins, J.B. (2006). Adiponectin--a key adipokine in the metabolic syndrome. Diabetes Obesity Metabol. 8, 264-280. https://doi.org/10.1111/j.1463-1326.2005.00510.x
  46. Wong, G.W., Krawczyk, S.A., Kitidis-Mitrokostas, C., Ge, G., Spooner, E., Hug, C., Gimeno, R., and Lodish, H.F. (2009). Identification and characterization of CTRP9, a novel secreted glycoprotein, from adipose tissue that reduces serum glucose in mice and forms heterotrimers with adiponectin. FASEB J. 23, 241-258. https://doi.org/10.1096/fj.08-114991
  47. Wu, S., Kasisomayajula, K., Peng, J., and Bancalari, E. (2009). Inhibition of JNK enhances TGF-beta1-activated Smad2 signaling in mouse embryonic lung. Pediatric Res. 65, 381-386. https://doi.org/10.1203/PDR.0b013e3181991c67
  48. Xia, Z., Dickens, M., Raingeaud, J., Davis, R.J., and Greenberg, M.E. (1995). Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270, 1326-1331. https://doi.org/10.1126/science.270.5240.1326
  49. Zhan, Y., Kim, S., Izumi, Y., Izumiya, Y., Nakao, T., Miyazaki, H., and Iwao, H. (2003). Role of JNK, p38, and ERK in platelet-derived growth factor-induced vascular proliferation, migration, and gene expression. Arterioscler. Thromb. Vasc. Biol. 23, 795-801. https://doi.org/10.1161/01.ATV.0000066132.32063.F2
  50. Zheng, Q., Yuan, Y., Yi, W., Lau, W.B., Wang, Y., Wang, X., Sun, Y., Lopez, B.L., Christopher, T.A., Peterson, J.M., et al. (2011) C1q/TNF-related proteins, a family of novel adipokines, induce vascular relaxation through the adiponectin receptor-1/AMPK/eNOS/nitric oxide signaling pathway. Arterioscler. Thromb. Vasc. Biol. 31, 2616-2623. https://doi.org/10.1161/ATVBAHA.111.231050