家族性原發性皮膚類澱粉沉積症 (Familial primary cutaneous amyloidosis, FPCA) 一種好發於東南亞及南美的慢性皮膚病，近年來已發現FPCA是由於角質細胞的IL-31 receptor-IL-31RA或oncostatin M receptor beta (OSMRb) subunit發生點突變而造成。一般皮膚角質細胞在受到IL-31的刺激時會促使MCP-1產生並吸引單核球及巨噬細胞來清除皮膚的細胞碎片，但當IL-31 receptor發生突變後，MCP-1的產生量會下降而導致細胞碎片無法清除，最後累積而造成皮膚類澱粉沉積的現象發生。FPCA現有的治療方法以塗抹外用類固醇 (corticosteroids) 及服用抗組織胺藥物為主，但病症大多有復發的情形。
在本篇研究中建立了以人類皮膚角質細胞 (HaCaT) 轉殖mutant IL-31RA的細胞株作為一個篩藥平台，用以找出可提升IL-31RA突變細胞株中MCP-1的藥物，進而達到改善家族性原發性皮膚類澱粉沉積症的目的，並進一步確認藥物的作用機制。
在藥物篩選結果發現MEK1/2 kinase inhibitor可提升IL-31RA突變細胞MCP-1產量。此外，上市的MEK1/2 kinase inhibitor, Trametinib, 也能夠提升IL-31RA突變細胞MCP-1產量；除了MCP-1產量以外，MCP-1 mRNA表現量在加入藥物後同樣有看到提升的現象。而MCP-1 promoter的轉錄因子之一- phospho-STAT1 (Tyr 701) 在加入藥物後，發現表現量有顯著增加的情形。
根據這些結果可推測藉由抑制MEK1/2的活性會增加phospho-STAT1 (Tyr701) 的表現，phospho-STAT1 (Tyr701) 作為transcription activator結合到MCP-1 promoter增加MCP-1 mRNA的表現量，進而提升IL-31RA突變細胞的MCP-1產量，顯示MEK1/2在調控IL-31RA突變細胞的MCP-1產量扮演著相當重要的角色，未來期待能更進一步研究MEK1/2與家族性原發型皮膚類澱粉沉積症的關聯性，也期待與現有療法搭配能更有助於疾病的改善與減少復發的情形

Primary cutaneous amyloidosis (PCA) is a chronic skin disease that most frequently occurs in Southeast Asia and South America. Based on the etiology, PCA can be classified into sporadic and familial types. Recently, mutations on IL-31RA or oncostatin M receptor β (OSMRβ) gene have been found to correlate with familial primary cutaneous amyloidosis (FPCA). MCP-1, upon induction by IL-31 can recruit monocytes/macrophages to clean the cell debris on the skin. However, when certain mutations occur in IL-31 receptor, the levels of MCP-1 would decrease, leading to the accumulation of cell debris on the surface of skin.
In this study, a cell-based drug screening system was established in which human keratinocyte cells (HaCaT) were transfected with mutant IL-31RA plasmid. In lieu of this system, several potential activators of MCP-1 in IL-31RA mutant cells were discovered. Subsequently, the underlying mechanism was explored.
Results from this study showed that the levels of MCP-1 were increased by MEK1/2 kinase inhibitors, PD 198306 or Trametinib. The expression levels of MCP-1 mRNA increased when the cells were treated with PD 198306. The expression levels phospho-STAT1 (Tyr701), one transcription factor of MCP-1 promoter, were also significantly increased when the HaCaT cells harboring mutant IL-31RA were treated with either MEK1/2 kinase inhibitors.
Overall, these results might suggest that inhibition of MEK1/2 activity might increase the expression levels of phospho-STAT1 (Tyr701). The phospho-STAT1 (Tyr701) can act as a transcription activator and bind on MCP-1 promoter to enhance the transcription. Although the exact interplays between MEK1/2 and FPCA remains to be further investigated, this study indicate that MEK1/2 pathway may be a novel target for development of effective FPCA treatment.

[1] M. W. Lin, D. D. Lee, T. T. Liu, Y. F. Lin, S. Y. Chen, C. C. Huang, et al., "Novel IL31RA gene mutation and ancestral OSMR mutant allele in familial primary cutaneous amyloidosis," Eur J Hum Genet, vol. 18, pp. 26-32, Jan 2010.
[2] K. Arita, A. P. South, G. Hans-Filho, T. H. Sakuma, J. Lai-Cheong, S. Clements, et al., "Oncostatin M receptor-beta mutations underlie familial primary localized cutaneous amyloidosis," Am J Hum Genet, vol. 82, pp. 73-80, Jan 2008.
[3] C. H. Shiao YM, Chen CC, Chiang KN, Chang YT, Lee DD, Lin MW, Tsai SF, Matsuura I, "MCP-1 as an effector of IL-31 signaling in familial primary cutaneous amyloidosis.," J Invest Dermatol, 2013.
[4] T. Murakami, N. Ishiguro, and K. Higuchi, "Transmission of Systemic AA Amyloidosis in Animals," Vet Pathol, vol. 51, pp. 363-71, Mar 2014.
[5] J. D. Sipe, M. D. Benson, J. N. Buxbaum, S. Ikeda, G. Merlini, M. J. Saraiva, et al., "Amyloid fibril protein nomenclature: 2010 recommendations from the nomenclature committee of the International Society of Amyloidosis," Amyloid, vol. 17, pp. 101-4, Sep 2010.
[6] R. S. Mitchell, V. Kumar, A. K. Abbas, and N. Fausto, Robbins Basic Pathology, 8 ed., 2007.
[7] L. M. Blancas-Mejia and M. Ramirez-Alvarado, "Systemic amyloidoses," Annu Rev Biochem, vol. 82, pp. 745-74, 2013.
[8] R. A. Kyle and M. A. Gertz, "Primary systemic amyloidosis: clinical and laboratory features in 474 cases," Semin Hematol, vol. 32, pp. 45-59, Jan 1995.
[9] W. Ollague, J. Ollague, and H. Ferretti, "Epidemiology of primary cutaneous amyloidoses in South America," Clin Dermatol, vol. 8, pp. 25-9, Apr-Jun 1990.
[10] T. Tan, "Epidemiology of primary cutaneous amyloidoses in southeast Asia," Clin Dermatol, vol. 8, pp. 20-4, Apr-Jun 1990.
[11] W. Ollague, "Primary cutaneous amyloidosis," Int J Dermatol, vol. 26, p. 135, Mar 1987.
[12] B. S. Qiu, "[715 cases of primary cutaneous amyloidosis]," Zhonghua Yi Xue Za Zhi, vol. 64, pp. 554-7, Sep 1984.
[13] D. B. Vasily, S. G. Bhatia, and S. R. Uhlin, "Familial primary cutaneous amyloidosis. Clinical, genetic, and immunofluorescent studies," Arch Dermatol, vol. 114, pp. 1173-6, Aug 1978.
[14] D. D. Lee, C. K. Huang, P. C. Ko, Y. T. Chang, W. Z. Sun, and Y. J. Oyang, "Association of primary cutaneous amyloidosis with atopic dermatitis: a nationwide population-based study in Taiwan," Br J Dermatol, vol. 164, pp. 148-53, Jan 2011.
[15] J. Borowicz, M. Gillespie, and R. Miller, "Cutaneous amyloidosis," Skinmed, vol. 9, pp. 96-100; quiz 101, Mar-Apr 2011.
[16] W. D. James, T. Berger, and D. M. Elston, Andrews' Diseases of the Skin, 11 ed., 2006.
[17] C. K. Wong, "Lichen amyloidosus. A relatively common skin disorder in Taiwan," Arch Dermatol, vol. 110, pp. 438-40, Sep 1974.
[18] C. Errol, "Lichen amyloidosis of the auricular concha: report of two cases and review of the literature," Dermatol Online J, vol. 12, p. 1, 2006.
[19] V. Eswaramoorthy, I. Kaur, A. Das, and B. Kumar, "Macular amyloidosis: etiological factors," J Dermatol, vol. 26, pp. 305-10, May 1999.
[20] S. A. Ritchie, T. Beachkofsky, S. Schreml, A. Gaspari, and C. M. Hivnor, "Primary localized cutaneous nodular amyloidosis of the feet: a case report and review of the literature," Cutis, vol. 93, pp. 89-94, Feb 2014.
[21] C. K. Wong and C. S. Lin, "Friction amyloidosis," Int J Dermatol, vol. 27, pp. 302-7, Jun 1988.
[22] Y. T. Chang, C. K. Wong, K. C. Chow, and C. H. Tsai, "Apoptosis in primary cutaneous amyloidosis," Br J Dermatol, vol. 140, pp. 210-5, Feb 1999.
[23] Y. T. Chang, H. N. Liu, C. K. Wong, K. C. Chow, and K. Y. Chen, "Detection of Epstein-Barr virus in primary cutaneous amyloidosis," Br J Dermatol, vol. 136, pp. 823-6, Jun 1997.
[24] H. Furumoto, Y. Hashimoto, M. Muto, T. Shimizu, and K. Nakamura, "Apolipoprotein E4 is associated with primary localized cutaneous amyloidosis," J Invest Dermatol, vol. 119, pp. 532-3, Aug 2002.
[25] Y. T. Chang, S. F. Tsai, W. J. Wang, C. J. Hong, C. Y. Huang, and C. K. Wong, "A study of apolipoproteins E and A-I in cutaneous amyloids," Br J Dermatol, vol. 145, pp. 422-7, Sep 2001.
[26] P. F. Cheung, C. K. Wong, A. W. Ho, S. Hu, D. P. Chen, and C. W. Lam, "Activation of human eosinophils and epidermal keratinocytes by Th2 cytokine IL-31: implication for the immunopathogenesis of atopic dermatitis," Int Immunol, vol. 22, pp. 453-67, Jun 2010.
[27] Q. Zhang, P. Putheti, Q. Zhou, Q. Liu, and W. Gao, "Structures and biological functions of IL-31 and IL-31 receptors," Cytokine Growth Factor Rev, vol. 19, pp. 347-56, Oct-Dec 2008.
[28] S. Kasraie, M. Niebuhr, K. Baumert, and T. Werfel, "Functional effects of interleukin 31 in human primary keratinocytes," Allergy, vol. 66, pp. 845-52, Jul 2011.
[29] M. Shen, S. Siu, S. Byrd, K. H. Edelmann, N. Patel, R. R. Ketchem, et al., "Diverse functions of reactive cysteines facilitate unique biosynthetic processes of aggregate-prone interleukin-31," Exp Cell Res, vol. 317, pp. 976-93, Apr 15 2011.
[30] C. Cornelissen, J. Luscher-Firzlaff, J. M. Baron, and B. Luscher, "Signaling by IL-31 and functional consequences," Eur J Cell Biol, vol. 91, pp. 552-66, Jun-Jul 2012.
[31] S. L. Deshmane, S. Kremlev, S. Amini, and B. E. Sawaya, "Monocyte chemoattractant protein-1 (MCP-1): an overview," J Interferon Cytokine Res, vol. 29, pp. 313-26, Jun 2009.
[32] A. Yadav, V. Saini, and S. Arora, "MCP-1: chemoattractant with a role beyond immunity: a review," Clin Chim Acta, vol. 411, pp. 1570-9, Nov 11 2010.
[33] P. Sartipy and D. J. Loskutoff, "Monocyte chemoattractant protein 1 in obesity and insulin resistance," Proc Natl Acad Sci U S A, vol. 100, pp. 7265-70, Jun 10 2003.
[34] J. Panee, "Monocyte Chemoattractant Protein 1 (MCP-1) in obesity and diabetes," Cytokine, vol. 60, pp. 1-12, Oct 2012.
[35] J. H. Gong, L. G. Ratkay, J. D. Waterfield, and I. Clark-Lewis, "An antagonist of monocyte chemoattractant protein 1 (MCP-1) inhibits arthritis in the MRL-lpr mouse model," J Exp Med, vol. 186, pp. 131-7, Jul 7 1997.
[36] C. R. Chong and D. J. Sullivan, Jr., "New uses for old drugs," Nature, vol. 448, pp. 645-6, Aug 9 2007.
[37] N. D. Yeomans, "Aspirin: old drug, new uses and challenges," J Gastroenterol Hepatol, vol. 26, pp. 426-31, Mar 2011.
[38] J. I. Sirven, "New Uses for Older Drugs: The Tales of Aspirin, Thalidomide, and Gabapentin," Mayo Clinic Proceedings, vol. 85, pp. 508-511, 2010.
[39] R. J. D'Amato, M. S. Loughnan, E. Flynn, and J. Folkman, "Thalidomide is an inhibitor of angiogenesis," Proc Natl Acad Sci U S A, vol. 91, pp. 4082-5, Apr 26 1994.
[40] A. Palumbo, T. Facon, P. Sonneveld, J. Blade, M. Offidani, F. Gay, et al., "Thalidomide for treatment of multiple myeloma: 10 years later," Blood, vol. 111, pp. 3968-77, Apr 15 2008.
[41] Y. Z. Patt, M. M. Hassan, R. D. Lozano, A. K. Nooka, Schnirer, II, J. B. Zeldis, et al., "Thalidomide in the treatment of patients with hepatocellular carcinoma: a phase II trial," Cancer, vol. 103, pp. 749-55, Feb 15 2005.
[42] J. H. Zhang, T. D. Chung, and K. R. Oldenburg, "A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays," J Biomol Screen, vol. 4, pp. 67-73, 1999.
[43] C. J. Wright and P. L. McCormack, "Trametinib: first global approval," Drugs, vol. 73, pp. 1245-54, Jul 2013.
[44] A. K. Salama and K. B. Kim, "Trametinib (GSK1120212) in the treatment of melanoma," Expert Opin Pharmacother, vol. 14, pp. 619-27, Apr 2013.
[45] N. Alluri and A. Jimeno, "Trametinib for the treatment of melanoma," Drugs Today (Barc), vol. 49, pp. 491-8, Aug 2013.
[46] R. Roskoski, Jr., "ERK1/2 MAP kinases: structure, function, and regulation," Pharmacol Res, vol. 66, pp. 105-43, Aug 2012.
[47] K. Maki and K. Ikuta, "MEK1/2 induces STAT5-mediated germline transcription of the TCRgamma locus in response to IL-7R signaling," J Immunol, vol. 181, pp. 494-502, Jul 1 2008.
[48] Y. Zhang, Y. Y. Cho, B. L. Petersen, F. Zhu, and Z. Dong, "Evidence of STAT1 phosphorylation modulated by MAPKs, MEK1 and MSK1," Carcinogenesis, vol. 25, pp. 1165-75, Jul 2004.
[49] Z. J. Tian and W. An, "ERK1/2 contributes negative regulation to STAT3 activity in HSS-transfected HepG2 cells," Cell Res, vol. 14, pp. 141-7, Apr 2004.
[50] N. Jain, T. Zhang, S. L. Fong, C. P. Lim, and X. Cao, "Repression of Stat3 activity by activation of mitogen-activated protein kinase (MAPK)," Oncogene, vol. 17, pp. 3157-67, Dec 17 1998.
[51] T. K. Sengupta, E. S. Talbot, P. A. Scherle, and L. B. Ivashkiv, "Rapid inhibition of interleukin-6 signaling and Stat3 activation mediated by mitogen-activated protein kinases," Proc Natl Acad Sci U S A, vol. 95, pp. 11107-12, Sep 15 1998.
[52] J. Chung, E. Uchida, T. C. Grammer, and J. Blenis, "STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation," Mol Cell Biol, vol. 17, pp. 6508-16, Nov 1997.
[53] N. Li, J. E. McLaren, D. R. Michael, M. Clement, C. A. Fielding, and D. P. Ramji, "ERK is integral to the IFN-gamma-mediated activation of STAT1, the expression of key genes implicated in atherosclerosis, and the uptake of modified lipoproteins by human macrophages," J Immunol, vol. 185, pp. 3041-8, Sep 1 2010.
[54] M. E. Condren and M. D. Bradshaw, "Ivacaftor: a novel gene-based therapeutic approach for cystic fibrosis," J Pediatr Pharmacol Ther, vol. 18, pp. 8-13, Jan 2013.
[55] M. J. Harrison, D. M. Murphy, and B. J. Plant, "Ivacaftor in a G551D homozygote with cystic fibrosis," N Engl J Med, vol. 369, pp. 1280-2, Sep 26 2013.
[56] E. D. Deeks, "Ivacaftor: a review of its use in patients with cystic fibrosis," Drugs, vol. 73, pp. 1595-604, Sep 2013.
[57] J. R. Infante, L. A. Fecher, G. S. Falchook, S. Nallapareddy, M. S. Gordon, C. Becerra, et al., "Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial," Lancet Oncol, vol. 13, pp. 773-81, Aug 2012.
[58] Q. An, L. Zhang, S. Zheng, J. Lin, Y. Hong, H. D. Chen, et al., "Thalidomide improves clinical symptoms of primary cutaneous amyloidosis: report of familiar and sporadic cases," Dermatol Ther, vol. 26, pp. 263-6, May-Jun 2013.
[59] J. Das and R. K. Gogoi, "Treatment of primary localised cutaneous amyloidosis with cyclophosphamide," Indian J Dermatol Venereol Leprol, vol. 69, pp. 163-4, Mar-Apr 2003.
[60] E. Ozkaya-Bayazit, C. Baykal, and A. Kavak, "[Local DMSO treatment of macular and papular amyloidosis]," Hautarzt, vol. 48, pp. 31-7, Jan 1997.
[61] M. H. Lien, D. Railan, and B. R. Nelson, "The efficacy of dermabrasion in the treatment of nodular amyloidosis," J Am Acad Dermatol, vol. 36, pp. 315-6, Feb 1997.
[62] A. G. Jin, A. Por, L. K. Wee, C. K. Kai, and G. C. Leok, "Comparative study of phototherapy (UVB) vs. photochemotherapy (PUVA) vs. topical steroids in the treatment of primary cutaneous lichen amyloidosis," Photodermatol Photoimmunol Photomed, vol. 17, pp. 42-3, Feb 2001.
[63] A. Lesiak, A. Rakowski, A. Brzezinska, M. Rogowski-Tylman, P. Kolano, A. Sysa-Jedrzejowska, et al., "Effective treatment of nodular amyloidosis with carbon dioxide laser," J Cutan Med Surg, vol. 16, pp. 372-4, Sep-Oct 2012.
[64] I. Hamzavi and H. Lui, "Excess tissue friability during CO2 laser vaporization of nodular amyloidosis," Dermatol Surg, vol. 25, pp. 726-8, Sep 1999.
[65] A. P. Truhan, J. M. Garden, and H. H. Roenigk, Jr., "Nodular primary localized cutaneous amyloidosis: immunohistochemical evaluation and treatment with the carbon dioxide laser," J Am Acad Dermatol, vol. 14, pp. 1058-62, Jun 1986.