Janus kinases (JAKs) are non-receptor tyrosine kinases that ultimately mediate the signal transduction of several key cytokines that help maintain the immune system and regulate hematopoiesis in humans. While a particular JAK deficiency has been identified in cases of autosomal recessive severe combined immunodeficiency, a hyperactive JAK pathway has pathological consequences as well, including myelo- and lympho-proliferative disorders, autoimmune diseases, and chronic inflammatory disorders like psoriasis and rheumatoid arthritis. In fact, the JAK pathway plays a major role in the signaling of cytokines responsible for the immune and inflammatory response in psoriasis, including interleukin (IL)-12, IL-17, and IL-23. Preclinical evidence and phase 2 trials have already shown the safety and efficacy of topical and small molecule oral JAK inhibitors in patients with chronic plaque psoriasis. Ongoing clinical studies are further evaluating the safety, efficacy, and durability of these investigational drugs. JAK inhibition provides another option for effective targeted-therapy for such a complex disease as psoriasis.
SchindlerC., StrehlowI.Cytokines and STAT signaling. Adv Pharmacol2000; 47: 113–74.
7.
KisselevaT., BhattacharyaS., BraunsteinJ., SchindlerC.W.Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene.2002; 285: 1–24.
8.
ManningG., WhyteD.B., MartinezR., HunterT., SudarsanamS.The protein kinase complement of the human genome. Science2002; 298: 1912–34.
9.
YehT.C., DondiE., UzeG., PellegriniS.A dual role for the kinase-like domain of the tyrosine kinase Tyk2 in interferon-alpha signaling. Proc Natl Acad Sci USA.2000; 97: 8991–6.
10.
RemyI., WilsonI.A., MichnickS.W.Erythropoietin receptor activation by a ligand-induced conformation change. Science.1999; 283: 990–3.
11.
SchindlerC.W.JAK-STAT signaling in human disease. J Clin Invest2002; 109: 1133–7.
RodigS.J., MerazM.A., WhiteJ.M.Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell.1998; 93: 373–83.
21.
IgazP., TothS., FalusA.Biological and clinical significance of the JAK-STAT pathway; lessons from knockout mice. Inflamm Res.2001; 50: 435–41.
22.
NeubauerH., CumanoA., MullerM., WuH., HuffstadtU., PfefferK.Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell.1998; 93: 397–409.
23.
ParganasE., WangD., StravopodisD.Jak2 is essential for signaling through a variety of cytokine receptors. Cell.1998; 93: 385–95.
24.
NosakaT., van DeursenJ.M., TrippR.A.Defective lymphoid development in mice lacking Jak3. Science.1995; 270: 800–2.
25.
ParkS.Y., SaijoK., TakahashiT.Developmental defects of lymphoid cells in Jak3 kinase-deficient mice. Immunity.1995; 3: 771–82.
26.
ThomisD.C., GurniakC.B., TivolE., SharpeA.H., BergLJ., BergL.J.Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking Jak3. Science.1995; 270: 794–7.
27.
MacchiP., VillaA., GilianiS.Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature.1995; 377: 65–8.
28.
RussellS.M., TayebiN., NakajimaH.Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Science.1995; 270: 797–800.
ShimodaK., KatoK., AokiK.Tyk2 plays a restricted role in IFN alpha signaling, although it is required for IL-12-medicated T cell function. Immunity.2000; 13: 561–71.
31.
YapG.S., OrtmannR., ShevachE., SherA.A heritable defect in IL-12 signaling in B10.Q/J mice. II. Effect on acute resistance to Toxoplasma gondii and rescue by IL-18 treatment. J Immunol.2001; 166: 5720–5.
32.
ShawM.H., BoyartchukV., WongS.A natural mutation in the Tyk2 pseudokinase domain underlies altered susceptibility of B10.Q/J mice to infection and autoimmunity. Proc Natl Acad Sci USA.2000; 100: 11594–9.
33.
KaraghiosoffM., SteinbornR., KovarikP.Central role for type I interferons and Tyk2 in lipopolysaccharide-induced endotoxin shock. Nat Immunol.2003; 4: 471–7.
34.
JamesC., UgoV., Le CouedicJ.P.A unique clonal JAK2 mutation leading to constitutive signaling causes polycythemia vera. Nature.2005; 434: 1144–8.
35.
KralovicsR., PassamontiF., BuserA.S.A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med.2005; 352: 1179–90.
36.
LevineR.L., WadleighM., CoolsJ.Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell.2005; 7: 387–97.
37.
BaxterE.J., ScottL.M., CampbellP.J.Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet.2005; 365: 1054–61.
38.
LacroniqueV., BoureuxA., ValleV.D.A TEL-JAK2 fusion protein with constitutive activity in human leukemia. Science.1997; 278: 1309–12.
39.
PeetersP., RaynaudS.D., CoolsJ.Fusion of TEL, the ETS-variant gene 6 (ETV6), to the receptor-associated kinase JAK2 as a result of t(9;12) in a lymphoid and t(9;15: 12) in a myeloid leukemia. Blood1997; 90: 2535–40.
40.
LeeJ.W., KimY.G., SoungY.H.The JAK2 V617F mutation in de novo acute myelogenous leukemias. Oncogene.2006; 25: 1434–6.
41.
JoosS., KupperM., OhlS.Genomic imbalances including amplication of the tyrosine kinase gene JAK2 in CD30+ Hodgkin cellsCancer Res.2000; 60: 452–549.
42.
WaltersD.K., MercherT., GuT.L.Activating alleles of JAK3 in acute megakaryoblastic leukemia. Cancer Cell.2006; 10: 65–75.
43.
De VitaS., MulliganC., McElwaineS.Loss-of-function JAK3 mutations in TMD and AMKL of Down syndrome. Br J Haematol2007; 137: 337–41.
44.
LovatoP., BrenderC., AgnholtJ.Constitutive STAT3 activation in intestinal T cells from patients from Crohn's disease. J Biol Chem2003; 278: 16777–81.
45.
IvashkivL.B., HuX.The JAK/STAT pathway in rheumatoid arthritis pathogenic or protective?Arthritis Rheum.2003; 48: 2092–6.
46.
NishioH., MatsuiK., TsujiH., TamuraA., SuzukiK.Immunolocalisation of the janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway in human epidermis. J Anat.2001; 198: 581–9.
47.
EriksenK.W., LovatoP., SkovL.Increase sensitivity to interferon-α in psoriatic T cells. J Invest Dermatol.2005; 125: 936–44.
48.
SigurdssonS., NordmarkG., GoringH.H.Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am J Hum Genet2005; 76: 528–37.
49.
NussenzveigR.H., CortesJ., SeverM.Imatinib mesylate therapy for polycythemia vera: final result of a phase II study initiated in 2009. Int J Hematol.2001; 90: 58–63.
50.
VerstovsekS., KantarjianH., PardananiA.INCB018424, an oral, selective JAK2 inhibitor, shows significant clinical activity in a phase I/II study in patients with primary myelofibrosis (PMF) and post polycythemia vera/essential thrombocythemia myelofibrosis (post-PV/ET MF). Blood.2007; 110: Abstr. 558
51.
VerstovsekS., KantarjianH., MesaR.A.Safety and efficacy of a JAK1 & JAK2 inhibitor, INCB018424, in myelofibrosis. N Engl J Med2010; 363: 1117–27.
52.
VerstovsekS., PassamontiF., RambaldiA.A phase 2 study of INCB018424, an oral, selective JAK1/JAK2 inhibitor, in patients with advanced polycythemia vera and essential thrombocytemia refractory to hydroxyurea. Blood.2009; 114: Abstr. 311
53.
WernigG., KharasM.G., OkabeR.Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. Cancer Cell.2008; 13: 311–20.
54.
PardananiA., GotlibJ.R., JamiesonC.A phase I study of TG101348 a selective JAK2 inhibitor, in myelofibrosis: clinical response is accompanied by significant reduction in JAK2V617F allele burden Blood.2009; 114: Abstr. 755
55.
HexnerE.O., SerdikoffC., JanM.Lestaurtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with myeloproliferative disorders. Blood.2008; 111: 5663–71.
56.
SantosF.P., KantarjianH.M., JainN.Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosisBlood.2010; 115: 1131–6.
57.
HexnerE.O., GoldbergJ.D., PrchalJ.T.A multicenter, open label Phase I/II study of CEP701 (Lestaurtinib) in adults with myelofibrosis; a report on phase I: a study of the myeloproliferative disorders research consortium. Blood.2009; 114: Abstr. 754.
58.
PaquetteR., SokolL., ShahN.P.A phase I study of XL019, a selective JAK2 inhibitor, in patients with polycythemia vera. Blood.2008; 112: Abstr. 2810.
59.
ShahN., OlszynskiP., SokolL.A phase I study of XL019, a selective JAK2 inhibitor, in patients with primary myelofibrosis, post-polycythemia vera, or post-essential thrombocythemia myelofibrosis. Blood.2008; 112: Abstr. 98.
60.
VerstovsekS., OdenikeO., ScottB.Phase I dose-escalation trial of SB1518, a novel JAk2/FLT3 inhibitor, in acute and chronic myeloid diseases, including primary or post-essential thrombocythemia/polycythemia vera myelofibrosis. Blood.2009; 114: Abstr. 3905.
61.
HedvatM., HuszarD., HerrmannA.The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors. Cancer Cell.2009; 16: 487–97.
62.
PardananiA., LashoT., SmithG., BurnsC.J., FantinoE., TefferiA.CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients. Leukemia.2009; 23: 1441–5.
63.
TynerJ.W., BummT.G., DeiningerJ.CYT387, a novel JAK2 inhibitor, induces hematologic responses and normalizes inflammatory cytokines in murine myeloproliferative neoplasms. Blood.2010; 115: 5232–40.
64.
PardananiA., GeorgeG., LashoT.A Phase I/II study of CYT387, an oral JAK-1/2 inhibitor, in myelofibrosis: significant response rates in anemia, splenomegaly, and constitutional symptoms. Blood.2010; 117: Abstr. 460.
65.
ChangelianP.S., FlanaganM.E., BallD.J.Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Science.2003; 302: 875–8.
66.
JiangJ.K., GhoreschiK., DeflorianF.Examining the chirality, conformation and selective kinase inhibition of 3-(3R, 4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile(CP-690,550). J Med Chem.2008; 51: 8012–8.
67.
Quintas-CardamaA., KantarjianH., CortesJ., VerstovsekS.Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond. Nature Reviews Drug Discovery.2011; 10: 127–40.
68.
GaspariA.A.Innate and adaptive immunity and pathophysiology of psoriasis. J Am Acad Dermatol.2006; 54: S67–80.
69.
BowcockA.M., KruegerJ.G.Getting under the skin: the immunogenetics of psoriasis. Nat Rev Immunol.2005; 5: 699–711.
70.
Di CesareA., Di MeglioP., NestleF.O.The IL-23/Th17 axis in the immunopathogenesis of psoriasis. J Invest Dermatol.2009; 129: 1339–50.
71.
HofmannS.R., EttingerR., ZhouY.J.Cytokines and their role in lymphoid development, differentiation and homeostasis. Cur Opin Aller Clin Immunol.2002; 2: 495–506.
72.
NickoloffBJ., NickoloffB.J.Cracking the cytokine code in psoriasis. Nat Med.2007; 13: 242–4.
73.
ChanJ.R., BlumenscheinW., MurphyE.IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis. J Exp Med.2006; 203: 2577–87.
74.
ZhengY., DanilenkoD.M., ValdezP.Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature.2007; 445: 648–51.
75.
IshizakiM., AkimotoT., MuromotoR.Involvement of tyrosine kinase-2 in both the IL-12/Th1 and IL-23/Th17 axes in vivo. J Immunol.2011; 187: 181–9.
76.
BaconC.M., McVicarD.W., OrtaldoJ.R., ReesR.C., O'SheaJ.J., JohnstonJ.A.Interleukin 12 (IL-12) induces tyrosine phosphorylation and JAK2 and TYK2: differential use of Janus family tyrosine kinases by IL-2 and IL-12. J Exp Med.1995; 181: 399–404.
77.
FierlbeckG., RassnerG., MullerC.Psoriasis induced at the injection site of recombinant interferon gamma. Results of immunohistologic investigations. Arch Dermatol.1990; 126: 351–5.
78.
KornT., BettelliE., OukkaM., KuchrooV.K.IL-17 and Th17 cells. Annu Rev Immunol.2009; 27: 485–517.
79.
NogralesK.E., ZabaL.C., Guttman-YasskyE.Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways. Br J Dermatol.2008; 159: 1092–102.
80.
OuyangW., KollsJ.K., ZhengY.The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity.2008; 28: 454–67.
81.
CaproniM., AntigaE., MelaniL., VolpiW., Del BiancoE., FabbriP.Serum level s of IL-17 and IL-22 are reduced by etanercept, but not by acitretin, in patients with psoriasis: a randomized-controlled trial. J Clin Immunol.2009; 29: 210–4.
82.
AricanO., AralM., SasmazS., CiragilP.Serum levels of TNF-alpha, IFN-gamma, IL-6, IL-8, IL-12, IL-17, and IL-18 in patients with active psoriasis and correlation with disease severity. Mediators Inflamm.2005; 2005: 273–9.
83.
ZhouL., IvanovI.I., SpolskiR.IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol.2007; 8: 967–74.
84.
AggarwalS., GhilardiN., XieM.H., de SauvageF.J., GurneyA.L.Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem.2003; 278: 1910–4.
85.
Vanden EijndenS., GorielyS., De WitD., WillemsF., GoldmanM.IL-23 upregulates IL-10 and induces IL-17 synthesis by polyclonally activated naïve T cells in human. Eur J Immunol.2005; 35: 469–75.
86.
LowesM.A., KikuchiT., Fuentes-DuculanJ.Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. J Invest Dermatol.2008; 128: 1207–11.
FridmanJ.S., ScherleP.A., CollinsR.Preclinical evaluation of local JAK1 and JAK2 inhibition in cutaneous inflammation. J Invest Dermatol.2011; 131: 1838–44.
90.
PunwaniN., ScherleP., FloresR.Preliminary clinical activity of a topical JAK1/2 inhibitor in the treatment of psoriasis. J Am Acad Dermatol. doi. 10.1016/j.jaad. 2011.12.018. Published online January 24, 2012.
91.
PunwaniN., WilliamsW., ScherleP.Initial efficacy and safety of topical INCB018424 cream, a selective Janus kinase 1 and 2 (JAK1&2) inhibitor in psoriasis. Poster session presented at: American Academy of Dermatology 67th Annual Meeting. 2009 March 6–10; San Francisco, CA.
92.
WilliamsN.K., BamertR.S., PatelO.Dissecting specificity in the janus kinases: the structures of jak-specific inhibitors complexed to the JAK1 and JAK2 protein tyrosine kinase domains. J Mol Biol.2009; 387: 219–32.
van GurpE., WeimarW., GastonR.Phase I dose escalation study of CP-690,550 in stable renal allograft recipients: Preliminary findings of safety, tolerability, effects on lymphocyte subsets and pharmacokinetics. Am J Transplant.2008; 8: 1711–8.
95.
van GurpE.A., Schoordijk-VerschoorW., KlepperM.The effect of the JAK inhibitor CP-690,550 on peripheral immune parameters in stable kidney allograft patients. Transplantation.2009; 87: 78–86.
96.
BusqueS., LeventhalJ., BrennanD.C.Calcineurin-inhibitor-free immunosuppression based on the JAK inhibitor CP-690,550: a pilot study in de novo kidney allograft recipients. Am J Transplant.2009; 9: 1936–45.
97.
KremerJ.M., BloomB.J., BreedveldF.C.The safety and efficacy of a JAK inhibitor in patients with active Rheumatoid arthritis. Arthritis Rheum.2009; 60: 1895–905.
98.
CoombsJ.H., BloomB.J., BreedveldF.C.Improved pain, physical functioning, and health status in rheumatoid arthritis patients treated with CP-690,550, an orally active Janus kinase (JAK) inhibitor: results from a randomized, double-blind, placebo-controlled trial. Ann Rheum Dis.2009; 69: 413–6.
99.
BoyM.G., WangC., WilkinsonB.E.Double-blind, placebo-controlled, dose-escalation study to evaluate the pharmacologic effect of CP-690,550 in patients with psoriasis. J Invest Dermatol.2009; 129: 2299–303.
100.
HarnessJ., PappK., MenterA., HuamingT.Tasocitinib (CP-690,550), an oral Janus kinase inhibitor, significantly improves the symptoms of moderate-to-severe psoriasis with short-term treatment. Poster session presented at: European Academy of Dermatology and Venereology. 2010 October 6–10. Gothenburg, Sweden.
101.
CohenS., ZwillichS.H., ChowV., LabadieR.R., WilkinsonB.Co-administration of the JAK inhibitor CP-690,550 and methotrexate is well tolerated in patients with rheumatoid arthritis without need for dose adjustment. Br J Clin Pharmacol.2010; 69: 143–51.
102.
KremerJ.M., CohenS., WilkinsonB.E.A Phase IIb Dose-ranging study of the oral JAK inhibitor Tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone. Arthritis Rheum.2012; 64: 970–81.
