*Immunomodulatory Effect of Methotrexate Abruptly Controls Keratinocyte Activation in Psoriasis DOI: http://dx.doi.org/10.5772/intechopen.102811*

[77] Tomic-Canic M, Komine M, Freedberg IM, et al. Epidermal signal transduction and transcription factor activation in activated keratinocytes. Journal of Dermatological Science. 1998;**17**(3):167-181

[78] Freedberg IM, Tomic-Canic M, Komine M, et al. Keratins and the keratinocyte activation cycle. Journal of Investigative Dermatology. 2001;**116**(5):633-640

[79] Ma S, Rao L, Freedberg IM, Blumenberg M. Transcriptional control of K5, K6, K14, and K17 keratin genes by AP-1 and NF-kappaB family members. Gene Expression. 1997;**6**(6):361-370

[80] Jiang CK, Flanagan S, Ohtsuki M. Disease-activated transcription factor: Allergic reactions in human skin cause nuclear translocation of STAT-91 and induce synthesis of keratin K17. Molecular and Cellular Biology. 1994;**14**(7):4759-4769

[81] Jiang CK, Tomic-Canic M, Lucas DJ, et al. TGF beta promotes the basal phenotype of epidermal keratinocytes: Transcriptional induction of K#5 and K#14 keratin genes. Growth Factors. 1995;**12**(2):87-97

[82] Zepter K, Haffner A, De Soohoo LF, et al. Induction of biologically active IL-1 beta converting enzyme and mature IL-1 beta in human keratinocytes by inflammatory and immunologic stimuli. Journal of Immunology. 1997;**159**(12):6203-6208

[83] Corsini E, Primavera A, Marinovich M, Galli CL. Selective induction of cell associated interleukin-1alpha in murine keratinocytes by chemical allergens. Toxicology. 1998;**129**(2-3):193-200

[84] Murphy JE, Robert C, Kupper TS. Interleukin-1 and cutaneous

inflammation: A crucial link between innate and acquired immunity. Journal of Investigative Dermatology. 2000;**114**(3):602-608

[85] Romero LI, Zhang DN, Herron GS, Karasek MA. Interleukin-1 induces major phenotypic changes in human skin microvascular endothelial cells. Journal of Cellular Physiology. 1997;**173**(1):84-92

[86] Wyble CW, Hynes KL, Kuchibhotla J, et al. TNF alpha and IL-1 upregulate membrane-bound and soluble E-selectin through a common pathway. Journal of Surgical Research. 1997;**73**(2):107-112

[87] Santamaria Babi LF, Moser R, Perez Soler MT. Migration of skin-homing T cells across cytokine-activated human endothelial cell layers involves interaction of the cutaneous lymphocyteassociated antigen (CLA), the very late antigen-4 (VLA-4), and the lymphocyte function associated antigen-1 (LFA-1). Journal of Immunology. 1995;**154**(4):1543-1550

[88] Maas-Szabowski N, Fusenig NE. Interleukin-1-induced growth factor expression in postmitotic and resting fibroblasts. Journal of Investigative Dermatology. 1996;**107**(6):849-855

[89] Kolde G, Schulze-Osthoff K, Meyer H, et al. Immunohistological and immunoelectron microscopic identification of TNF alpha in normal human and murine epidermis. Archives of Dermatological Research. 1992;**284**(3):154-158

[90] Griffiths TW, Griffiths CE, Voorhees JJ. Immunopathogenesis and immunotherapy of psoriasis. Dermatologic Clinics. 1995;**13**(4):739-749

[91] Nickoloff BJ, Griffiths CE, Barker JN. The role of adhesion molecules, chemotactic factors, and cytokines in

inflammatory and neoplastic skin disease. Journal of Investigative Dermatology. 1990;**94**(Suppl. 6):151S-157S

[92] Kupper TS. Role of epidermal cytokines. In: Oppenheim JJ, Shevach EM, editors. Immunophysiology. The Role of Cells and Cytokines in Immunity and Inflammation. London and New York: Oxford University Press; 1990. pp. 285-305

[93] Marinkovich MP, Lunstrum GP, Keene DR, et al. The dermal-epidermal junction of human skin contains a novel laminin variant. Journal of Cell Biology. 1992;**119**(3):695-703

[94] Burgeson RE. Type VII collagen, anchoring fibrils, and epidermolysis bullosa. Journal of Investigative Dermatology. 1993;**101**(3):252-255

[95] Troyanovsky SM, Leube RE, Franke WW. Characterization of the human gene encoding cytokeratin 17 and its expression pattern. European Journal of Cell Biology. 1992;**59**(1):127-137

[96] van Ruissen F, van Erp PEJ, de Jongh GJ. Cell kinetic characterization of growth arrest in cultured human keratinocytes. Journal of Cell Science. 1994;**107**(8):2219-2228

[97] Nockowski P, Szepietowski JC, Ziarkiewicz M. Serum concentrations of transforming growth factor beta 1 in patients with psoriasis vulgaris. Acta Dermatovenerologica Croatica. 2004;**12**(1):2-6

[98] Ryan TJ, Vickers HR, Salem SN, et al. The treatment of psoriasis with folic acid antagonist. The British Journal of Dermatology. 1964;**76**:555-564

[99] Boffa M, Chalmers R. Methotrexate for psoriasis. Clinical and Experimental Dermatology. 1996;**21**:399-408

[100] Bright R. Methotrexate in the treatment of psoriasis. Cutis. 1999;**64**:332-334

[101] Strober BE, Menon K. Folate supplementation during methotrexate therapy for patients with psoriasis. Journal of the American Academy of Dermatology. 2005;**53**:652-659

[102] Gubner R, August S, Ginsberg V. Therapeutic suppression of tissue reactivity. II. Effect of aminopterin in rheumatoid arthritis and psoriasis. The American Journal of the Medical Sciences. 1951;**221**:176-182

[103] Ward JR. Historical perspective on the use of methotrexate for the treatment of rheumatoid arthritis. Journal of Rheumatology. 1985;**12**:3-6

[104] Cronstein BN. Molecular therapeutics: Methotrexate and its mechanism of action. Arthritis and Rheumatism. 1996;**39**:1951-1960

[105] Lynch JP III, McCune J. Immunosuppressive and cytotoxic pharmacotherapy for pulmonary disorders. American Journal of Respiratory Critical Care Medicine. 1997;**155**:395-420

[106] Kremer JM. Methotrexate update. Scandinavian Journal of Rheumatology. 1996;**25**(6):341-344

[107] Goodman TA, Polisson RP. Methotrexate: Adverse reactions and major toxicities. Rheumatic Diseases Clinics of North America. 1994;**20**:513-528

[108] Chan ES, Cronstein BN. Methotrexate—how does it really work? Nature Reviews Rheumatology. 2010;**6**:175-178

[109] Griffiths CEM, Clark CM, Chalmers RJG, et al. A systematic review *Immunomodulatory Effect of Methotrexate Abruptly Controls Keratinocyte Activation in Psoriasis DOI: http://dx.doi.org/10.5772/intechopen.102811*

of treatments for severe psoriasis. Health Technology Assessment. 2000;**4**(40):1-125

[110] Callis KP, Chadha A, Vaishnaw A, et al. Reduction of CD45RO+ effector T lymphocytes is not observed in the treatment of psoriasis with methotrexate. Journal of Investigative Dermatology. 2002;**119**:244 (abstract 220)

[111] Elango T, Dayalan H, Subramanian S, Gnanaraj P, Malligarjunan H. Serum interleukin-6 levels in response to methotrexate treatment in psoriatic patients. Clinica Chimica Acta. 2012;**413**(19-20):1652-1656

[112] Elango T, Dayalan H, Gnanaraj P, Malligarjunan H, Subramanian S. Impact of methotrexate on oxidative stress and apoptosis markers in psoriatic patients. Clinical and Experimental Medicine. 2014;**14**(4):431-437

[113] Heydendael VM, Spuls PI, Opmeer BC, et al. Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis. The New England Journal of Medicine. 2003;**349**(7):658-665

[114] Sandhu K, Kaur I, Kumar B, et al. Efficacy and safety of cyclosporine versus methotrexate in severe psoriasis: A study from north India. Journal of Dermatology. 2003;**30**(6):458-463

[115] Gawkrodger DJ. On behalf of the Therapy Guidelines and Audit Subcommittee of the British Association of Dermatologists. Current management of psoriasis. Journal of Dermatological Treatment. 1997;**8**:27-55

[116] Said S, Jeffes EW, Weinstein GD. Methotrexate. Clinics in Dermatology. 1997;**15**(5):781-797

[117] Roenigk HH Jr, Auerbach R, Maibach HI. Methotrexate in psoriasis: Revised guidelines. Journal of the American Academy of Dermatology. 1988;**19**(1 pt1):145-156

[118] Roenigk HH Jr, Auerbach R, Maibach HI, et al. Methotrexate in psoriasis: Consensus conference. Journal of the American Academy of Dermatology. 1998;**38**(3):478-485

[119] Dogra S, Krishna V, Kanwar AJ. Efficacy and safety of systemic methotrexate in two fixed doses of 10. Clinical and Experimental Dermatology. 2012;**37**(7):729-734

[120] Yeo CM, Chong VH, Earnest A. Prevalence and risk factors of methotrexate hepatoxicity in Asian patients with psoriasis. World Journal of Hepatology. 2013;**5**(5):275-280

[121] Zachariae H. Have methotrexateinduced liver fibrosis and cirrhosis become rare? A matter for reappraisal of routine liver biopsies. Dermatology. 2005;**211**(4):307-308

[122] Kremer JM. Methotrexate treatment of rheumatic diseases: Can we do better? Arthritis and Rheumatism. 2008;**58**:3279-3282

[123] Wessels JA, Huizinga TW, Guchelaar HJ. Recent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis. Rheumatology (Oxford). 2008;**47**:249-255

[124] Sigmundsdottir H, Johnston A, Gudjonsson JE, et al. Methotrexate markedly reduces the expression of vascular E-selectin, cutaneous lymphocyte-associated antigen and the numbers of mononuclear leucocytes in psoriatic skin. Experimental Dermatology. 2004;**13**(7):426-434

[125] Jeffes EW III, McCullough JL, Pittelkow MR, et al. Methotrexate

therapy of psoriasis: Differential sensitivity of proliferating lymphoid and epithelial cells to the cytotoxic and growth-inhibitory effects of methotrexate. Journal of Investigative Dermatology. 1995;**104**(2):183-188

[126] Phillips DC, Woollard KJ, Griffiths HR. The anti-inflammatory actions of methotrexate are critically dependent upon the production of reactive oxygen species. British Journal of Pharmacology. 2003;**138**(3):501-511

[127] Herman S, Zurgil N, Deutsch M. Low dose methotrexate induces apoptosis with reactive oxygen species involvement in T lymphocytic cell lines to a greater extent than in monocytic lines. Inflammation Research. 2005;**54**(7):273-280

[128] Magari K, Miyata S, Nishigaki F. Differential effects of FK506 and methotrexate on inflammatory cytokine levels in rat adjuvant-induced arthritis. Journal of Rheumatology. 2003;**30**(10):2193-2200

[129] Partsch G, Steiner G, Leeb BF. Highly increased levels of tumor necrosis factor-alpha and other proinflammatory cytokines in psoriatic arthritis synovial fluid. Journal of Rheumatology. 1997;**24**(3):518-523

[130] Gerards AH, de Lathouder S, de Groot ER. Inhibition of cytokine production by methotrexate. Studies in healthy volunteers and patients with rheumatoid arthritis. Rheumatology (Oxford, England). 2003;**42**(10):1189-1196

[131] Barsig J, Yam G, Lehner MD, Beume R. Methotrexate treatment suppresses local cytokine and chemokine production in rat adjuvant arthritis. Drugs under Experimental and Clinical Research. 2005;**31**(1):7-11

[132] Seitz M, Loetscher P, Dewald B, et al. Methotrexate action in rheumatoid arthritis: Stimulation of cytokine inhibitor and inhibition of chemokine production by peripheral blood mononuclear cells. British Journal of Rheumatology. 1995;**34**(7):602-609

[133] Partsch G, Wagner E, Leeb BF, et al. T cell derived cytokines in psoriatic arthritis synovial fluids. Annals of the Rheumatic Diseases. 1998;**57**(11):691-693

[134] Neurath MF, Hildner K, Becker C et al. "Methotrexate specifically modulates cytokine production by T cells and macrophages in murine collagen-induced arthritis (CIA): A mechanism for methotrexate-mediated immunosuppression". Clinical and Experimental Immunology. 1999;**115**(1):42-55

[135] Hildner K, Finotto S, Becker C, et al. Tumor necrosis factor (TNF) production by T cell receptor primed T lymphocytes is a target for low dose methotrexate in rheumatoid arthritis. Clinical and Experimental Immunology. 1999;**118**(1):137-146

[136] Constantin A, Loubet-Lescoulie P, Lambert N, et al. Antiinflammatory and immunoregulatory action of methotrexate in the treatment of rheumatoid arthritis: Evidence of increased interleukin-4 and interleukin-10 gene expression demonstrated in vitro by competitive reverse transcriptase polymerase chain reaction. Arthritis and Rheumatism. 1998;**41**(1):48-57

[137] Dolhain RJ, Tak PP, Dijkmans BA, et al. Methotrexate reduces inflammatory cell numbers, expression of monokines and of adhesion molecules in synovial tissue of patients with rheumatoid arthritis. British Journal of Rheumatology. 1998;**37**(5):502-508

*Immunomodulatory Effect of Methotrexate Abruptly Controls Keratinocyte Activation in Psoriasis DOI: http://dx.doi.org/10.5772/intechopen.102811*

[138] Kraan MC, Reece RJ, Barg EC, et al. Modulation of inflammation and metalloproteinase expression in synovial tissue by leflunomide and methotrexate in patients with active rheumatoid arthritis. Findings in a prospective, randomized, double-blind, parallel design clinical trial in thirty-nine patients at two centers. Arthritis and Rheumatism. 2000;**43**(8):1820-1830

[139] Bouma MG, van den Wildenberg FA, Buurman WA. Adenosine inhibits cytokine release and expression of adhesion molecules by activated human endothelial cells. The American Journal of Physiology. 1996;**270**(2Pt1):C522-C529

[140] Yamasaki E, Soma Y, Kawa Y, Mizoguchi M. Methotrexate inhibits proliferation and regulation of the expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 by cultured human umbilical vein endothelial cells. The British Journal of Dermatology. 2003;**149**(1):30-38

[141] Morhenn VB, Orenberg EK, Kaplan J, et al. Inhibition of a Langerhans cell mediated immune response by treatment modalities useful in psoriasis. Journal of Investigative Dermatology. 1983;**81**(1):23-27

[142] Liu HN, Wong CK. In vitro immunosuppressive effects of methotrexate and azathioprine on Langerhans cells. Archives of Dermatological Research. 1997;**289**(2):94-97

[143] Griffiths CE. T-cell-targeted biologicals for psoriasis. Current Drug Targets. Inflammation and Allergy. 2004;**3**(2):157-161

[144] Wrone-Smith T, Mitra RS, Thompson CB, et al. Keratinocytes derived from psoriatic plaques are

resistant to apoptosis compared with normal skin. The American Journal of Pathology. 1997;**151**(5):1321-1329

[145] Watt FM, Hogan BL. Out of Eden: Stem cells and their niches. Science. 2000;**287**:1427-1430

[146] Taylor G, Lehrer MS, Jensen PJ, et al. Involvement of follicular stem cells in forming not only the follicle but also the epidermis. Cell. 2000;**102**(4):451-461

[147] Oshima H, Rochat A, Kedzia C, et al. Morphogenesis and renewal of hair follicles from adult multipotent stem cells. Cell. 2001;**104**(2):233-245

[148] Huelsken J, Vogel R, Erdmann B, et al. β-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell. 2001;**105**(4):533-545

[149] Werner S, Smola H. Paracrine regulation of keratinocyte proliferation and differentiation. Trends in Cell Biology. 2001;**11**(4):143-146

[150] Kaufman CK, Fuchs E. It's got you covered. NF-kappaB in the epidermis. Journal of Cell Biology. 2000;**149**(5):999-1004

[151] Arnold I, Watt FM. c-Myc activation in transgenic mouse epidermis results in mobilization of stem cells and differentiation of their progeny. Current Biology. 2001;**11**(8):558-568

[152] Mee JB, Cork M, di Giovineb FS, et al. Interleukin-1: A key inflammatory mediator in psoriasis? Cytokine. 2006;**33**(2):72-78

[153] Tamilselvi E, Haripriya D, Hemamalini M, Pushpa G, Swapna S. Association of disease severity with IL-1 levels in methotrexate-treated psoriasis patients. Scandinavian Journal of Immunology. 2013;**78**(6):545-553

[154] Takematsu H, Terui K, Ohkohchi H, et al. Interleukin-1-like activity in horny layer extracts: Decreased activity in scale extracts of psoriasis and sterile dermatoses. Dermatologica. 1986;**172**:236

[155] Takematsu H, Tagam H. Lack of correlation interleukin 1 levels between interleukin 6 in psoriatic lesional skin. Tohoku Journal of Experimental Medicine. 1994;**172**:243-252

[156] Yoshinaga Y, Higaki M, Terajima S. Detection of inflammatory cytokines in psoriatic skin. Archives of Dermatological Research. 1995;**287**:158-164

[157] Debets R, Hegmans JP, Croughs P, et al. The IL-1 system in psoriatic skin. IL-1 antagonist sphere of influence in lesional psoriatic epidermis. Journal of Immunology. 1997;**158**(2955):± 63

[158] Fantini F, Magnoni C, Bracci-Laudiero L, Pincelli C. Nerve growth factor is increased in psoriatic skin. Journal of Investigative Dermatology. 1995;**105**:854-855

[159] Pincelli C. Nerve growth factor and keratinocytes: A role in psoriasis. European Journal of Dermatology. 2000;**10**(2):85-90

[160] Ockenfels HM, Nussbaum G, Schneck B, et al. The effect of cyclosporin A and FK 506 on the cAMP content in psoriatic keratinocytes. Skin Pharmacology and Physiology. 1996;**9**(4):281-288

[161] Kobayashi Y, Appella E, Yamada M, et al. Phosphorylation of Intracellular Precursors of Human IL-1. Journal of lmmunology. 1988;**14**:2279

[162] Barrera P, Boerbooms AM, Demacker PN, et al. Circulating concentrations and production of cytokines and soluble receptors in rheumatoid arthritis patients: Effects of a single dose Methotrexate. British Journal of Rheumatology. 1994;**33**:1017-1024

[163] Stamp LK, Hazlett J, Roberts RL, et al. Adenosine receptor expression in rheumatoid synovium: A basis for methotrexate action. Arthritis Research & Therapy. 2012;**14**:138

[164] Debets R, Hegmans JP, Troost RJ, et al. Enhanced production of biologically active interleukin-1a and interleukin-1b by psoriatic epidermal cells ex vivo: Evidence of increased cytosolic interleukin-1b levels and facilitated interleukin-1 release. European Journal of Immunology. 1995;**25**:1624-1630

[165] Yang CM, Luo SF, Hsieh HL, et al. Interleukin-1beta induces ICAM-1 expression enhancing leukocyte adhesion in human rheumatoid arthritis synovial fibroblasts: Involvement of ERK, JNK, AP-1, and NF-kappaB. Journal of Cellular Physiology. 2010;**224**(2):516-526

[166] Pietrzak AT, Zalewska A, Chodorowska G, et al. Invited critical review: Cytokines and anticytokines in psoriasis. Clinica Chimica Acta. 2008;**394**:7-21

[167] Martinon F, Tschopp J. Inflammatory caspases and inflammasomes: Master switches of inflammation. Cell Death and Differentiation. 2007;**14**:10-22

[168] Salskov-Iversen ML, Johansen C, Kragballe K. Caspase-5 expression is upregulated in lesional psoriatic skin. Journal of Investigative Dermatology. 2011;**131**(3):670-676

[169] Mizutani H, Ohmoto Y, Mizutani T, et al. Role of increased production of monocytes TNF-alpha, IL-1beta and IL-6 in psoriasis: Relation to focal

*Immunomodulatory Effect of Methotrexate Abruptly Controls Keratinocyte Activation in Psoriasis DOI: http://dx.doi.org/10.5772/intechopen.102811*

infection, disease activity and responses to treatments. Journal of Dermatological Science. 1997;**14**(2):145-153

[170] Chang DM, Weinblatt ME, Schur PH. The effects of methotrexate on interleukin 1 in patients with rheumatoid arthritis. Journal of Rheumatology. 1992;**19**:1678-1682

[171] Brody M, Böhm I, Bauer R. Mechanism of action of methotrexate: Experimental evidence that methotrexate blocks the binding of interleukin 1 beta to the interleukin 1 receptor on target cells. European journal of clinical chemistry. 1993;**31**(10):667-674

[172] Beta-Csorgo Z, Hammerberg C, Voorhees JJ, Cooper KD. Intralesional T-lymphocyte activation as a mediator of psoriatic hyperplasia. Journal of Investigative Dermatology. 1995;**105**:89S-894S

[173] Dinarello CA, Ikejima T, Warner SJ, et al. Interleukin 1 induces interleukin 1. I. Induction of circulating interleukin 1 in rabbits in vivo and in human mononuclear cells in vitro. Journal of Immunology. 1987;**139**:1902

[174] Thirupathi A, Elango T, Subramanian S, Gnanaraj P. Methotrexate regulates Th-1 response by suppressing caspase-1 and cytokines in psoriasis patients. Clinica Chimica Acta. 2016;**453**:164-169

[175] Bradley JR. TNF-mediated inflammatory disease. Journal of Pathology. 2008;**214**:149-160

[176] Shifa Z, Junping L, Yakun W, et al. Expressions of TNF receptors, ICAM-1 and LFA-1 in lesional skin of psoriasis vulgaris. Chinese Journal of Dermatology. 1998;**31**(2):84-86

[177] Mussi A, Bonifati C, Carducci M, et al. Serum TNF-alpha levels correlate with disease severity and are reduced by effective therapy in plaque-type psoriasis. Journal of Biological Regulators and Homeostatic Agents. 1997;**11**(3):115-118

[178] Chodorowska G. Plasma concentrations of IFN-gamma and TNF-alpha in psoriatic patients before and after local treatment with dithranol ointment. Journal of the European Academy of Dermatology and Venereology. 1998;**10**(2):147-151

[179] Johansen C, Funding AT, Otkjaer K, et al. Protein expression of TNF-alpha in psoriatic skin is regulated at a posttranscriptional level by MAPKactivated protein kinase 2. Journal of Immunology. 2006;**176**(3):1431-1438

[180] Majumdar S, Aggarwal BB. Methotrexate suppresses NfkappaB activation through inhibition of IkappaBalpha phosphorylation and degradation. Journal of Immunology. 2001;**167**:2911-2920

[181] Christophers E. The immunopathology of psoriasis. International Archives of Allergy and Immunology. 1996;**110**:199-206

[182] Abdallah MA, Abdel-Hamid MF, Kotb AM, Mabrouk EA. Serum interferon-gamma is a psoriasis severity and prognostic marker. Cutis. 2009;**84**(3):163-168

[183] Uyemura K, Yamamura M, Fivenson DF, Modlin RL. The cytokine network in lesional and lesion-free psoriatic skin is characterized by a T-helper type 1 cell-mediated response. Journal of Investigative Dermatology. 1993;**101**:701-705

[184] Schlaak JF, Buslau M, Jochum W, et al. T cells involved in psoriasis vulgaris belong to the Th1 subset. Journal of Investigative Dermatology. 1994;**102**:145-149

[185] El Barnawi NY, Ciasuddin ASM, Ziu MM, Singh M. Serum cytokine levels in psoriasis vulgaris. British Journal of Biomedical Science. 2001;**58**:40-44

[186] Arican O, Aral M, Sasmaz S, et al. Serum levels of TNF-alpha, IFNgamma, IL-6, IL-8, IL-12, IL-17, and IL-18 in patients with active psoriasis and correlation with disease severity. Mediators of Inflammation. 2005;**5**:273-279

[187] Piskin G, Koomen CW, Picavet D. Ultraviolet-B irradiation decreases IFN-γ and increases IL-4 expression in psoriatic lesional skin in situ and in cultured dermal T cells derived from these lesions. Experimental Dermatology. 2003;**12**:172-180

[188] Bonifati C, Trento E, Cordiali-Fei P, et al. Increased interleukin-7 concentrations in lesional skin and in the sera of patients with plaque-type psoriasis. Clinical Immunology and Immunopathology. 1997;**83**:41-44

[189] Nesher G, Moore TL. The in vitro effects of methotrexate on peripheral blood mononuclear cells. Modulation by methyl donors and spermidine. Arthritis and Rheumatism. 1990;**33**:954-959

[190] Kagami S, Rizzo HL, Lee JJ, et al. Circulating Th17, Th22, and Th1 cells are increased in psoriasis. Journal of Investigative Dermatology. 2010;**130**(5):1373-1383

[191] Rangarajan A, Talora C, Okuyama R, et al. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. The EMBO Journal. 2001;**20**(13):3427-3436

[192] Cutroneo KR. TGF-beta-induced fibrosis and SMAD signaling: Oligo decoys as natural therapeutics for inhibition of tissue fibrosis and scarring. Wound Repair and Regeneration. 2007;**15**(1):S54-S60

[193] Flisiak I, Porebski P, Flisiak R, Chodynicka B. Plasma transforming growth factor beta1 as a biomarker of psoriasis activity and treatment efficacy. Biomarkers. 2003;**8**(5):437-443

[194] Conery AR, Cao Y, Thompson EA, et al. Akt interacts directly with Smad3 to regulate the sensitivity to TGF-beta induced apoptosis. Nature Cell Biology. 2004;**6**(4):366-372

[195] Song K, Wang H, Krebs T, Danielpour D. Novel roles of Akt and mTOR in suppressing TGF-b/ALK5 mediated Smad3 activation. The EMBO Journal. 2006;**25**:58-69

[196] Ulloa L, Doody J, Massagué J. Inhibition of transforming growth factor-beta/SMAD signaling by the interferon-gamma/STAT pathway. Nature. 1999;**397**(6721):710-713

[197] Bitzer M, von Gersdorff G, Liang D, et al. A mechanism of suppression of TGF-beta/SMAD signaling by NF-kappa B/RelA. Genes & Development. 2000;**14**(2):187-197

[198] Cai JP, Falanga V, Taylor JR, Chin YH. Transforming growth factor beta receptor binding and function are decreased in posriatic dermal endothelium. Journal of Investigative Dermatology. 1996;**106**:225-231

[199] Winter-Vann AM, Kamen BA, Bergo MO, et al. Targeting Ras signaling through inhibition of carboxyl methylation: An unexpected property of Methotrexate. Proceedings of the National Academy of Sciences. 2003;**100**(11):6529-6534

[200] Simpson CL, Patel DM, Green KJ. Deconstructing the skin: Cytoarchitectural determinants of epidermal morphogenesis. Nature

*Immunomodulatory Effect of Methotrexate Abruptly Controls Keratinocyte Activation in Psoriasis DOI: http://dx.doi.org/10.5772/intechopen.102811*

Reviews. Molecular Cell Biology. 2011;**12**:565-580

[201] Huang WY, Yang PM, Chang YF, Marquez VE, Chen CC. Methotrexate induces apoptosis through p53/ p21-dependent pathway and increases E-cadherin expression through downregulation of HDAC/ EZH2. Biochemical Pharmacology. 2011;**81**(4):510-517

[202] Yugawa T, Handa K, Narisawa-Saito M, Ohno S, Fujita M, Kiyono T. Regulation of Notch1 gene expression by p53 in epithelial cells. Molecular and Cellular Biology. 2007;**27**(10):3732-3742

[203] Sriuranpong V, Borges MW, Ravi RK, et al. Notch signaling induces cell cycle arrest in small cell lung cancer cells. Cancer Research. 2001;**61**(7):3200-3205

[204] Miyoshi K, Takaishi M, Nakajima K, et al. Stat3 as a therapeutic target for the treatment of psoriasis: A clinical feasibility study with STA-21, a Stat3 inhibitor. Journal of Investigative Dermatology. 2011;**131**(1):108-117

[205] Meephansan J, Ruchusatsawat K, Sindhupak W, Thorner PS, Wongpiyabovorn J. Effect of methotrexate on serum levels of IL-22 in patients with psoriasis. European Journal of Dermatology. 2011;**21**(4):501-504

[206] Spurlock CF, Aune ZT, Tossberg JT, et al. Increased sensitivity to apoptosis induced by methotrexate is mediated by JNK. Arthritis and Rheumatism. 2011;**63**(9):2606-2616

[207] Neradil J, Pavlasova G, Veselska R. New mechanisms for an old drug; DHFRand non-DHFR-mediated effects of methotrexate in cancer cells. Klinická Onkologie. 2012;**2**:S87-S92

[208] Paradisi A, Pasquariello N, Barcaroli D, Maccarrone M. Anandamide regulates keratinocyte differentiation by inducing DNA methylation in a CB1 receptor-dependent manner. Journal of Biological Chemistry. 2008;**283**(10):6005-6012

[209] Leigh IM, Navsaria H, Purkis PE, et al. Keratins (K16 and K17) as markers of keratinocyte hyperproliferation in psoriasis in vivo and in vitro. The British Journal of Dermatology. 1995;**133**:501-511

[210] Fu M, Wang G. Keratin 17 as a therapeutic target for the treatment of psoriasis. Journal of Dermatological Science. 2012;**67**(3):161-165

[211] Li Y, Jiang L, Zhang S, Yin L, et al. Methotrexate attenuates the Th17/IL-17 levels in peripheral blood mononuclear cells from healthy individuals and RA patients. Rheumatology International. 2012;**32**(8):2415-2422
