사람 모유두세포에서 코르티코트로핀분비인자에 의한 모발성장관련사이토카인의 발현 조절 Corticotropin-Releasing Factor Down-Regulates Hair Growth-Related Cytokines in Cultured Human Dermal Papilla Cells원문보기
코르티코트로핀분비인자(Corticotropin-releasing factor)는 스트레스 반응에 관여하는 호르몬으로, 최근 스트레스가 탈모와 같은 피부질환에 영향을 미친다는 보고들이 많아지고 있다. 보고에 따르면, 사람 모낭 배양에서 코르티코트로핀분비인자는 길이생장을 억제하며, 모낭의 조기퇴행을 유도하고 모기질각질형성세포(hair matrix keratinocyte)의 세포사멸을 촉진시킨다. 본 연구에서는 코르티코트로핀분비인자가 모발성장과 모주기조절에 핵심적으로 역할하는 모유두세포에 미치는 영향에 대해 알아보고자 했다. 시상하부-뇌하수체-부신축의 주요 스트레스호르몬들인 코르티코트로핀분비인자, 부신피질자극호르몬, 그리고 코르티솔을 사람 모유두세포에 처리하였다. 흥미롭게도, 코르티코트로핀분비인자가 모발성장과 관련된 사이토카인(KGF, Wnt5a, $TGF{\beta}-2$, Nexin)의 발현을 변화시키는 것을 관찰하였으며, 세포 내 cAMP의 수준을 증가시켰고, 수용체의 발현을 억제시켰다. 이러한 변화는 수용체의 길항제인 antalarmin과 astressin2B, 또는 PKA 억제제의 전처리로 인해 막을 수 있었다. 코르티코트로핀분비인자는 cAMP/PKA경로를 통해 POMC의 발현을 유도하는데, 사람 모유두세포에서도 이 호르몬의 처리가 POMC mRNA의 발현을 증가시키는 것을 확인할 수 있었으나 부신피질자극호르몬의 변화는 western blot으로는 확인할 수 없었다. 이러한 결과들을 바탕으로, 코르티코트로핀분비인자가 그 수용체를 통해 사람 모유두세포 내 모발성장 관련 사이토카인의 발현을 조절함을 확인하였으며, 이는 코르티코트로핀분비인자의 수용체 길항제가 스트레스성 탈모환자를 위한 치료제 혹은 화장품 소재로써 활용될 수 있음을 보여준다.
코르티코트로핀분비인자(Corticotropin-releasing factor)는 스트레스 반응에 관여하는 호르몬으로, 최근 스트레스가 탈모와 같은 피부질환에 영향을 미친다는 보고들이 많아지고 있다. 보고에 따르면, 사람 모낭 배양에서 코르티코트로핀분비인자는 길이생장을 억제하며, 모낭의 조기퇴행을 유도하고 모기질각질형성세포(hair matrix keratinocyte)의 세포사멸을 촉진시킨다. 본 연구에서는 코르티코트로핀분비인자가 모발성장과 모주기조절에 핵심적으로 역할하는 모유두세포에 미치는 영향에 대해 알아보고자 했다. 시상하부-뇌하수체-부신축의 주요 스트레스호르몬들인 코르티코트로핀분비인자, 부신피질자극호르몬, 그리고 코르티솔을 사람 모유두세포에 처리하였다. 흥미롭게도, 코르티코트로핀분비인자가 모발성장과 관련된 사이토카인(KGF, Wnt5a, $TGF{\beta}-2$, Nexin)의 발현을 변화시키는 것을 관찰하였으며, 세포 내 cAMP의 수준을 증가시켰고, 수용체의 발현을 억제시켰다. 이러한 변화는 수용체의 길항제인 antalarmin과 astressin2B, 또는 PKA 억제제의 전처리로 인해 막을 수 있었다. 코르티코트로핀분비인자는 cAMP/PKA경로를 통해 POMC의 발현을 유도하는데, 사람 모유두세포에서도 이 호르몬의 처리가 POMC mRNA의 발현을 증가시키는 것을 확인할 수 있었으나 부신피질자극호르몬의 변화는 western blot으로는 확인할 수 없었다. 이러한 결과들을 바탕으로, 코르티코트로핀분비인자가 그 수용체를 통해 사람 모유두세포 내 모발성장 관련 사이토카인의 발현을 조절함을 확인하였으며, 이는 코르티코트로핀분비인자의 수용체 길항제가 스트레스성 탈모환자를 위한 치료제 혹은 화장품 소재로써 활용될 수 있음을 보여준다.
Corticotropin-releasing factor (CRF) is involved in the stress response and there is increasing evidence that stress influences skin disease such as hair loss. In cultured human hair follicles, CRF inhibits hair shaft elongation, induces premature regression and promotes the apoptosis of hair matrix...
Corticotropin-releasing factor (CRF) is involved in the stress response and there is increasing evidence that stress influences skin disease such as hair loss. In cultured human hair follicles, CRF inhibits hair shaft elongation, induces premature regression and promotes the apoptosis of hair matrix keratinocytes. We investigated whether CRF influences the dermal papilla cells (DPC) that play pivotal roles in hair growth and cycling. Human DPCs were treated with CRF, adrenocorticotropic hormone (ACTH) and cortisol, key stress hormones along the hypothalamic-pituitary -adrenal (HPA) axis for 1-24 h. Interestingly, CRF modulated the expression of cytokines related to hair growth (KGF, Wnt5a, $TGF{\beta}-2$, Nexin) and increased cAMP production in cultured DPCs. CRF receptors were down-regulated by negative feedback systems. Pretreatment of CRF receptor antagonists or protein kinase A (PKA) inhibitor prevented the CRF-induced modulation. Since the CRF induces proopiomelanocortin (POMC) expression through the cAMP/PKA pathway, we analyzed POMC mRNA. CRF stimulated POMC expression in cultured human DPCs, yet we were unable to detect ACTH levels by western blot. These results indicate that CRF operates within DPCs through CRF receptors along the classical CRF signaling pathway and CRF receptor antagonists could serve as potential therapeutic and cosmetic agents for stress-induced hair loss.
Corticotropin-releasing factor (CRF) is involved in the stress response and there is increasing evidence that stress influences skin disease such as hair loss. In cultured human hair follicles, CRF inhibits hair shaft elongation, induces premature regression and promotes the apoptosis of hair matrix keratinocytes. We investigated whether CRF influences the dermal papilla cells (DPC) that play pivotal roles in hair growth and cycling. Human DPCs were treated with CRF, adrenocorticotropic hormone (ACTH) and cortisol, key stress hormones along the hypothalamic-pituitary -adrenal (HPA) axis for 1-24 h. Interestingly, CRF modulated the expression of cytokines related to hair growth (KGF, Wnt5a, $TGF{\beta}-2$, Nexin) and increased cAMP production in cultured DPCs. CRF receptors were down-regulated by negative feedback systems. Pretreatment of CRF receptor antagonists or protein kinase A (PKA) inhibitor prevented the CRF-induced modulation. Since the CRF induces proopiomelanocortin (POMC) expression through the cAMP/PKA pathway, we analyzed POMC mRNA. CRF stimulated POMC expression in cultured human DPCs, yet we were unable to detect ACTH levels by western blot. These results indicate that CRF operates within DPCs through CRF receptors along the classical CRF signaling pathway and CRF receptor antagonists could serve as potential therapeutic and cosmetic agents for stress-induced hair loss.
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문제 정의
We demonstrated that activation of CRF receptors; CRF caused down-regulation of hair growth-related cytokines at the transcriptional level as well as the translational level in cultured human DPCs. To our knowledge, this is the first report to show operation of CRF via interaction of CRF receptors in cultured human DPCs.
가설 설정
Based on these previous facts, we hypothesized that CRF might influence the regulation of cytokines expression in human DPCs. Then, we found that CRF down-regulated hair growth-related cytokines through CRF receptor in DPCs.
제안 방법
It can be postulated that the primary target of oxidative damage in hair follicles could be origin of keratinocyte such as matrix cells and outer root sheath cells. We also evaluated the effect of CRF on human DPCs. We demonstrated that activation of CRF receptors; CRF caused down-regulation of hair growth-related cytokines at the transcriptional level as well as the translational level in cultured human DPCs.
후속연구
Fascinatingly, POMC expression was increased in human DPCs from 1 h after CRF treatment, yet the intracellular ACTH by CRF stimulation was unable to detect in cultured human DPC by western blot. Since POMC mRNA expression was induced by CRH, further investigations should attempt to clarify whether human DPCs show a fully functional peripheral HPA system. Outer root sheath (ORS) cells and DPCs are reported to support each other in hair follicles regarding cell proliferation, differentiation and migration[36, 37].
Outer root sheath (ORS) cells and DPCs are reported to support each other in hair follicles regarding cell proliferation, differentiation and migration[36, 37]. Therefore, further research into the co-culture of ORS cells and DPCs and effect of CRF on ORS cells are required for better understanding of the complex dynamics of hair follicles. In addition, it is necessary to confirm whether CRF activates Ca 2+ signaling pathway in human DPCs.
참고문헌 (37)
P. C. Arck, A. Slominski, T. C. Theoharides, E. M. Peters, and R. Paus, Neuroimmunology of stress: skin takes center stage, J. Invest. Dermatol., 126(8), 1697 (2006).
A. Slominski, J. Wortsman, T. Luger, R. Paus, and S. Solomon, Corticotropin releasing hormone and proopiomelanocortin involvement in the cutaneous response to stress, Physiol. Rev., 80(3), 979 (2000).
N. Ito, T. Ito, A. Kromminga, A. Bettermann, M. Takigawa, F. Kees, R. H. Straub, and R. Paus, Human hair follicles display a functional equivalent of the hypothalamic-pituitary-adrenal axis and synthesize cortisol, FASEB J., 19(10), 1332 (2005).
E. M. Peters, P. C. Arck, and R. Paus, Hair growth inhibition by psychoemotional stress: a mouse model for neural mechanisms in hair growth control, Exp. Dermatol., 15(1), 1 (2006).
A. Slominski, B. Zbytek, A. Szczesniewski, I. Semak, J. Kaminski, T. Sweatman, and J. Wortsman, CRH stimulation of corticosteroids production in melanocytes is mediated by ACTH, Am. J. Physiol. Endocrinol. Metab., 288(4), E701 (2005).
A. Slominski, A. Pisarchik, D. J. Tobin, J. E. Mazurkiewicz, and J. Wortsman, Differential expression of a cutaneous corticotropin-releasing hormone system, Endocrinology, 145(2), 941 (2004).
D. K. Grammatopoulos and G. P. Chrousos, Functional characteristics of CRH receptors and potential clinical applications of CRH-receptor antagonists, Trends Endocrinol. Metab., 13(10), 436 (2002).
A. Slominski, J. Wortsman, A. Pisarchik, B. Zbytek, E. A. Linton, J. E. Mazurkiewicz, and E. T. Wei, Cutaneous expression of corticotropin-releasing hormone (CRH), urocortin, and CRH receptors, FASEB J., 15(10), 1678 (2001).
R. L. Hauger, V. Risbrough, R. H. Oakley, J. A. Olivares-Reyes, and F. M. Dautzenberg, Role of CRF receptor signaling in stress vulnerability, anxiety, and depression, Ann. N. Y. Acad. Sci., 1179, 120 (2009).
K. W. Carlson, S. S. Nawy, E. T. Wei, W. Sade'e, V. A. Filov, V. V. Rezsova, A. Slominski, and J. M. Quillan, Inhibition of mouse melanoma cell proliferation by corticotropin-releasing hormone and its analogs, Anticancer Res., 21(2A), 1173 (2001).
M. E. Quevedo, A. Slominski, W. Pinto, E. Wei, and J. Wortsman, Pleiotropic effects of corticotropin releasing hormone on normal human skin keratinocytes, In Vitro Cell Dev. Biol. Anim., 37(1), 50 (2001).
B. Zbytek and A. T. Slominski, Corticotropin-releasing hormone induces keratinocyte differentiation in the adult human epidermis, J. Cell Physiol., 203(1), 118 (2005).
A. Katsarou-Katsari, L. K. Singh, and T. C. Theoharides, Alopecia areata and affected skin CRH receptor upregulation induced by acute emotional stress, Dermatology, 203(2), 157 (2001).
L. V. Spencer and J. P. Callen, Hair loss in systemic disease, Dermatol. Clin., 5(3), 565 (1987).
Y. Gauthier, [Stress and skin: experimental approach], Pathol. Biol. (Paris), 44(10), 882 (1996).
L. Wang, M. Million, J. Rivier, C. Rivier, N. Craft, M. P. Stenzel-Poore, and Y. Tache', CRF receptor antagonist astressin-B reverses and prevents alopecia in CRF over-expressing mice, PLoS One, 6(2), e16377 (2011).
P. C. Arck, B. Handjiski, E. M. Peters, A. S. Peter, E. Hagen, A. Fischer, B. F. Klapp, and R. Paus, Stress inhibits hair growth in mice by induction of premature catagen development and deleterious perifollicular inflammatory events via neuropeptide substance P-dependent pathways, Am. J. Pathol., 162(3), 803 (2003).
N. Liu, L. H. Wang, L. L. Guo, G. Q. Wang, X. P. Zhou, Y. Jiang, J. Shang, K. Murao, J. W. Chen, W. Q. Fu, and G. X. Zhang, Chronic restraint stress inhibits hair growth via substance P mediated by reactive oxygen species in mice, PLoS One, 8(4), e61574 (2013).
Z. Lu, T. W. Fischer, S. Hasse, K. Sugawara, Y. Kamenisch, S. Krengel, W. Funk, M. Berneburg, and R. Paus, Profiling the response of human hair follicles to ultraviolet radiation, J. Invest. Dermatol., 129(7), 1790 (2009).
S. J. Choi, A. R. Cho, S. J. Jo, S. T. Hwang, K. H. Kim, and O. S. Kwon, Effects of glucocorticoid on human dermal papilla cells in vitro, J. Steroid. Biochem. Mol. Biol., 135, 24 (2013).
L. Guo, L. Degenstein, and E. Fuchs, Keratinocyte growth factor is required for hair development but not for wound healing, Genes Dev., 10(2), 165 (1996).
D. M. Danilenko, B. D. Ring, D. Yanagihara, W. Benson, B. Wiemann, C. O. Starnes, and G. F. Pierce, Keratinocyte growth factor is an important endogenous mediator of hair follicle growth, development, and differentiation. Normalization of the nu/nu follicular differentiation defect and amelioration of chemotherapy-induced alopecia, Am. J. Pathol., 147(1), 145 (1995).
Y. Xing, W. Xu, K. Yang, X. Lian, and T. Yang, Immunolocalization of Wnt5a during the hair cycle and its role in hair shaft growth in mice, Acta. Histochem., 113(6), 608 (2011).
S. Reddy, T. Andl, A. Bagasra, M. M. Lu, D. J. Epstein, E. E. Morrisey, and S. E. Millar, Characterization of Wnt gene expression in developing and postnatal hair follicles and identification of Wnt5a as a target of Sonic hedgehog in hair follicle morphogenesis, Mech. Dev., 107(1-2), 69 (2001).
K. Inoue, N. Aoi, Y. Yamauchi, T. Sato, H. Suga, H. Eto, H. Kato, Y. Tabata, and K. Yoshimura, TGF-beta is specifically expressed in human dermal papilla cells and modulates hair folliculogenesis, J. Cell Mol. Med., 13(11-12), 4643 (2009).
K. Foitzik, T. Spexard, M. Nakamura, U. Halsner, and R. Paus, Towards dissecting the pathogenesis of retinoid-induced hair loss: all-trans retinoic acid induces premature hair follicle regression (catagen) by upregulation of transforming growth factor-beta2 in the dermal papilla, J. Invest. Dermatol., 124(6), 1119 (2005).
D. W. Yu, T. Yang, T. Sonoda, K. Gaffney, P. J. Jensen, T. Dooley, S. Ledbetter, I. M. Freedberg, R. Lavker, and T. T. Sun, Message of nexin 1, a serine protease inhibitor, is accumulated in the follicular papilla during anagen of the hair cycle, J. Cell Sci., 108(Pt 12), 3867 (1995).
A. Gidon, M. M. Al-Bataineh, F. G. Jean-Alphonse, H. P. Stevenson, T. Watanabe, C. Louet, A. Khatri, G. Calero, N. M. Pastor-Soler, T. J. Gardella, and J. P. Vilardaga, Endosomal GPCR signaling turned off by negative feedback actions of PKA and v-ATPase, Nat. Chem. Biol., 10(9), 707 (2014).
Y. Ni, J. Sinnett-Smith, S. H. Young, and E. Rozengurt, PKD1 mediates negative feedback of PI3K/Akt activation in response to G protein-coupled receptors, PLoS One, 8(9), e73149 (2013).
A. Limat, T. Hunziker, E. R. Waelti, S. P. Inaebnit, U. Wiesmann, and L. R. Braathen, Soluble factors from human hair papilla cells and dermal fibroblasts dramatically increase the clonal growth of outer root sheath cells, Arch. Dermatol. Res., 285(4), 205 (1993).
T. Fujie, S. Katoh, H. Oura, Y. Urano, and S. Arase, The chemotactic effect of a dermal papilla cell-derived factor on outer root sheath cells, J. Dermatol. Sci., 25(3), 206 (2001).
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