Targeting signaling pathways with small molecules to treat autoimmune disorders

References

• Monaco C, Andreakos E, Kiriakidis S, Feldmann M, Paleolog E. T-cell-mediated signalling in immune, inflammatory and angiogenic processes: the cascade of events leading to inflammatory diseases.Curr. Drug Targets Inflamm. Allergy3(1), 35–42 (2004).
   PubMedGoogle Scholar
• Gutcher I, Becher B. APC-derived cytokines and T cell polarization in autoimmune inflammation. J. Clin. Invest.117(5), 1119–1127 (2007).
   PubMed Web of Science ®Google Scholar
• Kinne RW, Brauer R, Stuhlmuller B et al. Macrophages in rheumatoid arthritis. Arthritis Res.2(3), 189–202 (2000).
   PubMedGoogle Scholar
• Feldmann M, Maini RN. TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases. Nat. Med.9(10), 1245–1249 (2003).
   PubMed Web of Science ®Google Scholar
• Garces K, Anakinra: interleukin-1 receptor antagonist therapy for rheumatoid arthritis. Issues Emerg. Health Technol.16, 1–4 (2001).
   Google Scholar
• Nishimoto N, Yoshizaki K, Miyasaka N et al. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum.50(6), 1761–1769 (2004).
   PubMed Web of Science ®Google Scholar
• Bouma G, Strober W. The immunological and genetic basis of inflammatory bowel disease. Nat. Rev. Immunol.3(7), 521–533 (2003).
   PubMed Web of Science ®Google Scholar
• Van Deventer SJ. Immunotherapy of Crohn’s disease. Scand. J. Immunol.51(1), 18–22 (2000).
   PubMedGoogle Scholar
• Bos JD, de Rie MA, Teunissen MB, Piskin G. Psoriasis: dysregulation of innate immunity. Br. J. Dermatol.152(6), 1098–1107 (2005).
   PubMed Web of Science ®Google Scholar
• Sibilia J. Psoriasis: skin and joints, same fight? J. Eur. Acad. Dermatol. Venereol.20(2), 56–72 (2006).
   Google Scholar
• Gottlieb AB. Psoriasis: emerging therapeutic strategies. Nat. Rev. Drug Discov.4(1), 19–34 (2005).
   PubMed Web of Science ®Google Scholar
• Harigai M, Hara M, Kawamoto M et al. Amplification of the synovial inflammatory response through activation of mitogen-activated protein kinases and nuclear factor κB using ligation of CD40 on CD14+ synovial cells from patients with rheumatoid arthritis. Arthritis Rheum.50(7), 2167–2177 (2004).
   PubMedGoogle Scholar
• Arrighi JF, Rebsamen M, Rousset F et al. A critical role for p38 mitogen-activated protein kinase in the maturation of human blood-derived dendritic cells induced by lipopolysaccharide, TNF-α, and contact sensitizers. J. Immunol.166(6), 3827 (2001).
   Google Scholar
• Aicher A, Shu GL, Magaletti D et al. Differential role for p38 mitogen-activated protein kinase in regulating CD40-induced gene expression in dendritic cells and B cells. J. Immunol.163(11), 5786–5795 (1999).
   PubMedGoogle Scholar
• Kyriakis JM, Avruch J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol. Rev.81(2), 807–869 (2001).
   PubMed Web of Science ®Google Scholar
• Tak PP, Firestein GS. NF-κB: a key role in inflammatory diseases. J. Clin. Invest.107(1), 7–11 (2001).
   PubMed Web of Science ®Google Scholar
• Symons A, Beinke S, Ley SC. MAP kinase kinase kinases and innate immunity. Trends Immunol.27, 40–48 (2006).
   PubMed Web of Science ®Google Scholar
• Pearson G, Robinson F, Beers Gibson T et al. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr. Rev.22(2), 153–183 (2001).
   PubMed Web of Science ®Google Scholar
• Rousseau S, Dolado I, Beardmore V et al. CXCL12 and C5a trigger cell migration via a PAK1/2-p38α MAPK-MAPKAP-K2-HSP27 pathway. Cell. Signal.18(11), 1897–1905 (2006).
   PubMed Web of Science ®Google Scholar
• Baldassare JJ, Bi Y, Bellone CJ. The role of p38 mitogen-activated protein kinase in IL-1-β transcription. J. Immunol.162(9), 5367–5373 (1999).
   PubMed Web of Science ®Google Scholar
• Shakhov AN, Collart MA, Vassalli P, Nedospasov SA, Jongeneel CV. κB-type enhancers are involved in lipopolysaccharide-mediated transcriptional activation of the tumor necrosis factor α gene in primary macrophages. J. Exp. Med.171(1), 35–47 (1990).
   PubMed Web of Science ®Google Scholar
• Yao J, Mackman N, Edgington TS, Fan S-T. Lipopolysaccharide induction of the tumor necrosis factor-α promoter in human monocytic cells. Regulation by Egr-1, c-Jun, and NF-κ-B transcription factors. J. Biol. Chem.272(22), 17795–17801 (1997).
   PubMed Web of Science ®Google Scholar
• Zagariya A, Mungre S, Lovis R et al. Tumor necrosis factor α gene regulation: enhancement of C/EBPβ-induced activation by c-Jun. Mol. Cell. Biol.18(5), 2815–2824 (1998).
   PubMedGoogle Scholar
• Kaminska B. MAPK signalling pathways as molecular targets for anti-inflammatory therapy – from molecular mechanisms to therapeutic benefits. Biochim. Biophys. Acta1754(1–2), 253–262 (2005).
   PubMed Web of Science ®Google Scholar
• Saccani S, Pantano S, Natoli G. p38-dependent marking of inflammatory genes for increased NF-κB recruitment. Nat. Immunol.3(1), 69–75 (2002).
   PubMed Web of Science ®Google Scholar
• Cuzzocrea S. Role of nitric oxide and reactive oxygen species in arthritis. Curr. Pharm. Des.12(27), 3551–3570 (2006).
   PubMed Web of Science ®Google Scholar
• Chan ED, Winston BW, Uh ST, Wynes MW, Rose DM, Riches DW. Evaluation of the role of mitogen-activated protein kinases in the expression of inducible nitric oxide synthase by IFN-γ and TNF-α in mouse macrophages. J. Immunol.162(1), 415–422 (1999).
   PubMed Web of Science ®Google Scholar
• Chen CC, Wang JK. p38 but not p44/42 mitogen-activated protein kinase is required for nitric oxide synthase induction mediated by lipopolysaccharide in RAW 264.7 macrophages. Mol. Pharmacol.55(3), 481–488 (1999).
   PubMed Web of Science ®Google Scholar
• Neininger A, Kontoyiannis D, Kotlyarov A et al. MK2 targets AU-rich elements and regulates biosynthesis of tumor necrosis factor and interleukin-6 independently at different post-transcriptional levels. J. Biol. Chem.277(5), 3065–3068 (2002).
   PubMed Web of Science ®Google Scholar
• Kotlyarov A, Neininger N, Schubert C et al. MAPKAP kinase 2 is essential for LPS-induced TNF-α biosynthesis. Nat. Cell Biol.1(2), 94–97 (1999).
   PubMed Web of Science ®Google Scholar
• Holtmann H, Winzen R, Holland P et al. Induction of interleukin-8 synthesis integrates effects on transcription and mRNA degradation from at least three different cytokine- or stress-activated signal transduction pathways. Mol. Cell. Biol.19(10), 6742–6753 (1999).
   PubMed Web of Science ®Google Scholar
• Holtmann H, Enninga J, Kalble S et al. The MAP kinase kinase TAK1 plays a central role in coupling the interleukin-1 receptor to both transcriptional and RNA-targeted mechanisms of gene regulation. J. Biol. Chem.276(5), 3508–3516 (2001).
   PubMed Web of Science ®Google Scholar
• Beyaert R, Cuenda A, Vanden-Berghe W et al. The p38/RK mitogen-activated protein kinase pathway regulates interleukin-6 synthesis response to tumor necrosis factor. EMBO J.15(8), 1914–1923 (1996).
   PubMed Web of Science ®Google Scholar
• Badger AM, Bradbeer JN, Votta B, Lee JC, Adams JL, Griswold DE. Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock, and immune function. J. Pharmacol. Exp. Ther.279(3), 1453–1461 (1996).
   PubMed Web of Science ®Google Scholar
• Tong L, Pav S, White DM et al. A highly specific inhibitor of human p38 MAP kinase binds in the ATP pocket. Nat. Struct. Biol.4(4), 311–316 (1997).
   PubMedGoogle Scholar
• Ward KW, Proksch JW, Azzarano LM et al. SB-239063, a potent and selective inhibitor of p38 map kinase: preclinical pharmacokinetics and species-specific reversible isomerization. Pharm. Res.18(9), 1336–1344 (2001).
   PubMed Web of Science ®Google Scholar
• Lee MR, Dominguez C. MAP kinase p38 inhibitors: clinical results and an intimate look at their interactions with p38α protein. Curr. Med. Chem.12(25), 2979–2994 (2005).
   PubMed Web of Science ®Google Scholar
• Branger J, van den Blink B, Weijer S et al. Anti-inflammatory effects of a p38 mitogen-activated protein kinase inhibitor during human endotoxemia. J. Immunol.168(8), 4070–4077 (2002).
   PubMed Web of Science ®Google Scholar
• Bianchi M, Ulrich P, Bloom O et al. An inhibitor of macrophage arginine transport and nitric oxide production (CNI-1493) prevents acute inflammation and endotoxin lethality. Mol. Med.1(3), 254–266 (1995).
   PubMed Web of Science ®Google Scholar
• Cohen PS, Nakshatri H, Dennis J et al. CNI-1493 inhibits monocyte/macrophage tumor necrosis factor by suppression of translation efficiency. Proc. Natl Acad. Sci. USA93(9), 3967–3971 (1996).
   PubMed Web of Science ®Google Scholar
• Zinser E, Turza N, Steinkasserer A. CNI-1493 mediated suppression of dendritic cell activation in vitro and in vivo. Immunobiology209(1–2), 89–97 (2004).
   PubMedGoogle Scholar
• Maroney AC, Finn JP, Connors TJ et al. Cep-1347 (KT7515), a semisynthetic inhibitor of the mixed lineage kinase family. J. Biol. Chem.276(27), 25302–25308 (2001).
   PubMed Web of Science ®Google Scholar
• Ciallella JR, Saporito M, Lund S et al. CEP-11004, an inhibitor of the SAPK/JNK pathway, reduces TNF-α release from lipopolysaccharide-treated cells and mice. Eur. J. Pharmacol.515(1–3), 179–187 (2005).
   PubMedGoogle Scholar
• Bennett BL, Sasaki DT, Murray BW et al. SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc. Natl Acad. Sci. USA98(24), 13681–13686 (2001).
   PubMed Web of Science ®Google Scholar
• Jackson JR, Bolognese B, Hillegass L et al. Pharmacological effects of SB 220025, a selective inhibitor of P38 mitogen-activated protein kinase, in angiogenesis and chronic inflammatory disease models. J. Pharmacol. Exp. Ther.284(2), 687–692 (1998).
   PubMed Web of Science ®Google Scholar
• Wadsworth SA, Cavender DE, Beers SA et al. RWJ 67657, a potent, orally active inhibitor of p38 mitogen-activated protein kinase. J. Pharmacol. Exp. Ther.291(2), 680–287 (1999).
   PubMed Web of Science ®Google Scholar
• van den Blink B, Juffermans NP, ten Hove T et al. p38 mitogen-activated protein kinase inhibition increases cytokine release by macrophages in vitro and during infection in vivo. J. Immunol.166(1), 582–587 (2001).
   PubMed Web of Science ®Google Scholar
• Faas MM, Moes H, Fijen JW et al. Monocyte intracellular cytokine production during human endotoxaemia with or without a second in vitro LPS challenge: effect of RWJ-67657, a p38 MAP-kinase inhibitor, on LPS-hyporesponsiveness. Clin. Exp. Immunol.127(2), 337–343 (2002).
   PubMed Web of Science ®Google Scholar
• Fijen JW, Zijlstra JG, de Boer P et al. Suppression of the clinical and cytokine response to endotoxin by RWJ-67657, a p38 mitogen-activated protein-kinase inhibitor, in healthy human volunteers. Clin. Exp. Immunol.124(1), 16–20 (2001).
   PubMed Web of Science ®Google Scholar
• Badger AM, Griswold DE, Kapadia R et al. Disease-modifying activity of SB 242235, a selective inhibitor of p38 mitogen-activated protein kinase, in rat adjuvant-induced arthritis. Arthritis Rheum.43(1), 175–183 (2000).
   PubMed Web of Science ®Google Scholar
• Wada Y, Nakajima-Yamada T, Yamada K et al. R-130823, a novel inhibitor of p38 MAPK, ameliorates hyperalgesia and swelling in arthritis models. Eur. J. Pharmacol.506(3), 285–295 (2005).
   PubMed Web of Science ®Google Scholar
• Mclay LM, Halley F, Souness JE et al. The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-arthritic efficacy. Bioorg. Med. Chem.9(2), 537–554 (2001).
   PubMed Web of Science ®Google Scholar
• Nishikawa M, Myoui A, Tomita T, Takahi K, Nampei A, Yoshikawa H. Prevention of the onset and progression of collagen-induced arthritis in rats by the potent p38 mitogen-activated protein kinase inhibitor FR167653. Arthritis Rheum.48(9), 2670–2681 (2003).
   PubMed Web of Science ®Google Scholar
• Mbalaviele G, Anderson G, Jones A et al. Inhibition of p38 mitogen-activated protein kinase prevents inflammatory bone destruction. J. Pharmacol. Exp. Ther.317(3), 1044–1053 (2006).
   PubMed Web of Science ®Google Scholar
• Kerlund K, Erlandsson-Harris H, Tracey KJ et al. Anti-inflammatory effects of a new tumour necrosis factor-α (TNF-α) inhibitor (CNI-1493) in collagen-induced arthritis (CIA) in rats. Clin. Exp. Immunol.115(1), 32–41 (1999).
   PubMedGoogle Scholar
• Larsson E, Harris HE, Palmblad K, Mansson B, Saxne T, Klareskog L. CNI-1493, an inhibitor of proinflammatory cytokines, retards cartilage destruction in rats with collagen induced arthritis. Ann. Rheum. Dis.64(3), 494–496 (2005).
   PubMedGoogle Scholar
• Han Z, Boyle DL, Chang L et al. c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J. Clin. Invest.108(2), 73–81 (2001).
   PubMed Web of Science ®Google Scholar
• Hollenbach E, Vieth M, Roessner A, Neumann M, Malfertheiner P, Naumann M. Inhibition of RICK/nuclear factor-κB and p38 signaling attenuates the inflammatory response in a murine model of Crohn disease. J. Biol. Chem.280(15), 14981–14988 (2005).
   PubMed Web of Science ®Google Scholar
• Hollenbach E, Neumann M, Vieth M, Roessner A, Malfertheiner P, Naumann M. Inhibition of p38 MAP kinase- and RICK/NF-κB-signaling suppresses inflammatory bowel disease. FASEB J.18(13), 1550–1552 (2004).
   PubMed Web of Science ®Google Scholar
• Hommes D, van den Blink B, Plasse T et al. Inhibition of stress-activated MAP kinases induces clinical improvement in moderate to severe Crohn’s disease. Gastroenterology122(1), 7–14 (2002).
   PubMed Web of Science ®Google Scholar
• Buchman AL, Katz S, Barish C, Elkin R, Korzenik J, Plasse T. Semapimod treatment of Crohn’s disease. Gastroenterology126(4), 464–465 (2004).
   Google Scholar
• Schreiber S, Feagan B, D’Haens G et al.; BIRB 796 Study Group. Oral p38 mitogen-activated protein kinase inhibition with BIRB 796 for active Crohn’s disease: a randomized, double-blind, placebo-controlled trial. Clin. Gastroenterol. Hepatol.4(3), 325–334 (2006).
   PubMed Web of Science ®Google Scholar
• Kaminska B, Gaweda-Walerych K, Zawadzka M. Molecular mechanisms of neuroprotective action of immunosuppressants – facts and hypotheses. J. Cell. Mol. Med.8(1), 45–58 (2004).
   PubMed Web of Science ®Google Scholar
• Matsuda S, Shibasaki F, Takehana K, Mori H, Nishida E, Koyasu S. Two distinct action mechanisms of immunophilin–ligand complexes for the blockade of T-cell activation. EMBO Rep.1(15), 428–434 (2005).
   Google Scholar
• Zawadzka M, Kaminska B. A novel mechanism of FK506 mediated neuroprotection: down-regulation of cytokine expression in glial cells. Glia49(1), 36–51 (2005).
   PubMed Web of Science ®Google Scholar
• Lichtiger S, Present DH, Kornbluth A et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N. Engl. J. Med.330(26), 1841–1845 (1994).
   PubMed Web of Science ®Google Scholar
• Egan LJ, Sandborn WJ, Tremaine WJ. Clinical outcome following treatment of refractory inflammatory and fistulizing Crohn’s disease with intravenous cyclosporine A. Am. J. Gastroenterol.93(3), 442–448 (1998).
   PubMed Web of Science ®Google Scholar
• McDonald JW, Feagan BG, Jewell D, Brynskov J, Stange EF, Macdonald JK. Cyclosporine for induction of remission in Crohn’s disease. Cochrane Database Syst. Rev.18(2), CD000297 (2005).
   Google Scholar
• Rafiee P, Johnson CP, Li MS et al. Cyclosporine A enhances leukocyte binding by human intestinal microvascular endothelial cells through inhibition of p38 MAPK and iNOS. J. Biol. Chem.277(38), 35605–35615 (2002).
   PubMed Web of Science ®Google Scholar
• Hogenauer C, Wenzl HH, Hinterleitner TA, Petritsch W. Effect of oral tacrolimus (FK 506) on steroid-refractory moderate/severe ulcerative colitis. Aliment. Pharmacol. Ther.18(4), 415–423 (2003).
   PubMed Web of Science ®Google Scholar
• Baumgart DC, Pintoffl JP, Sturm A, Wiedenmann B, Dignass AU. Tacrolimus is safe and effective in patients with severe steroid-refractory or steroid-dependent inflammatory bowel disease-a long-term follow-up. Am. J. Gastroenterol.101(5), 1048–1056 (2006).
   PubMed Web of Science ®Google Scholar
• Yoo SA, Park BH, Park GS et al. Calcineurin is expressed and plays a critical role in inflammatory arthrisis. J. Immunol.177(4), 2681–2690 (2006).
   PubMed Web of Science ®Google Scholar
• Magari K, Nishigaki F, Sasakawa T et al. Anti-arthritic properties of FK506 on collagen-induced arthritis in rats. Inflamm. Res.52(12), 524–529 (2003).
   PubMed Web of Science ®Google Scholar
• Kitahara K, Kawai S. Cyclosporine and tacrolimus for the treatment of rheumatoid arthritis. Curr. Opin. Rheumatol.19(3), 238–245 (2007).
   PubMed Web of Science ®Google Scholar
• Stuetz A, Grassberger M, Meingassner JG. Pimecrolimus (Elidel, SDZ ASM 981) – preclinical pharmacologic profile and skin selectivity. Semin. Cutan. Med. Surg.20(4), 233–241 (2001).
   PubMed Web of Science ®Google Scholar
• Scheinfeld N. The use of topical tacrolimus and pimecrolimus to treat psoriasis: a review. Dermatol. Online J.10(1), 3 (2004).
   PubMedGoogle Scholar
• Marsland AM, Griffiths CE. The macrolide immunosuppressants in dermatology: mechanisms of action. Eur. J. Dermatol.12, 618–622 (2002).
   PubMed Web of Science ®Google Scholar
• Meingassner JG, Fahrngruber H, Barandi A. SDZASM981, in contrast to CyA and FK 506, does not suppress the primary immune response in murine allergic contact dermatitis (abstract). J. Invest. Dermatol.114, 832 (2000).
   Google Scholar
• Rappersberger K, Komar M, Ebelin ME et al. Pimecrolimus identifies a common genomic anti-inflammatory profile, is clinically highly effective in psoriasis and is well tolerated. J. Invest. Dermatol.119(4), 876–887 (2002).
   PubMed Web of Science ®Google Scholar
• Korfitis C, Gregoriou S, Rallis E, Rigopoulos D. Pimecrolimus versus topical corticosteroids in dermatology. Expert Opin. Pharmacother.8(10), 1565–1573 (2007).
   PubMed Web of Science ®Google Scholar
• Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW. Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene285(1–2), 1–24 (2002).
   PubMed Web of Science ®Google Scholar
• Murray PJ. The JAK-STAT signaling pathway: input and output integration. J. Immunol.178(5), 2623–2629 (2007).
   PubMed Web of Science ®Google Scholar
• Pfitzner E, Kliem S, Baus D, Litterst CM. The role of STATs in inflammation and inflammatory diseases. Curr. Pharm. Des.10(23), 2839–2850 (2004).
   PubMed Web of Science ®Google Scholar
• Decker T, Stockinger S, Karaghiosoff M, Muller M, Kovarik P. IFNs and STATs in innate immunity to microorganisms. J. Clin. Invest.109(10), 1271–1277 (2002).
   PubMed Web of Science ®Google Scholar
• Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem. J.374(1), 1–20 (2003).
   PubMed Web of Science ®Google Scholar
• Watford WT, Hissong BD, Bream JH, Kanno Y, Muul L, O’Shea JJ. Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol. Rev.202, 139–156 (2004).
   PubMed Web of Science ®Google Scholar
• Donnelly RP, Sheikh F, Kotenko SV, Dickensheets H. The expanded family of class II cytokines that share the IL-10 receptor-2 (IL-10R2) chain. J. Leukoc. Biol.76, 314–321 (2004).
   PubMedGoogle Scholar
• Lin J-X, Leonard WJ. The role of Stat5a and Stat5b in signaling by IL-2 family cytokines. Oncogene19(21), 2566–2576 (2000).
   PubMed Web of Science ®Google Scholar
• Mudter J, Neurath MF. IL-6 signaling in inflammatory bowel disease: pathophysiological role and clinical relevance. Inflamm. Bowel Dis.13(8), 1016–1023 (2007).
   PubMed Web of Science ®Google Scholar
• Scheller Ohnesorge N, Rose-John S. Interleukin-6 trans-signalling in chronic inflammation and cancer. Scand. J. Immunol.63(5), 321–329 (2006).
   PubMed Web of Science ®Google Scholar
• Minegishi Y, Saito M, Morio T et al. Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity25(5), 745–755 (2006).
   PubMed Web of Science ®Google Scholar
• Kamezaki K, Shimoda K, Numata A, Matsuda T, Nakayama K, Harada M. The role of Tyk2, Stat1 and Stat4 in LPS-induced endotoxin signals. Int. Immunol.16(8), 1173–1179 (2004).
   PubMedGoogle Scholar
• Karaghiosoff M, Neubauer H, Lassnig C et al. Partial impairment of cytokine responses in Tyk2-deficient mice. Immunity13(4), 549–560 (2000).
   PubMed Web of Science ®Google Scholar
• Shaw MH, Boyartchuk V, Wong S et al. A natural mutation in the Tyk2 pseudokinase domain underlies altered susceptibility of B10 Q/J mice to infection and autoimmunity. Proc. Natl Acad. Sci. USA100(20), 11594–11599 (2003).
   PubMed Web of Science ®Google Scholar
• Matsukawa A. STAT proteins in innate immunity during sepsis: lessons from knockout mice. Acta Med. Okayama61(5), 239–245 (2007).
   PubMedGoogle Scholar
• Gao J, Morrison DC, Parmely TJ, Russell SW, Murphy WJ. An interferon-γ-activated site (GAS) is necessary for full expression of the mouse iNOS gene in response to interferon-γ and lipopolysaccharide. J. Biol. Chem.272(2), 1226–1230 (1997).
   PubMed Web of Science ®Google Scholar
• Nakahira M, Ahn HJ, Park WR et al. Synergy of IL-12 and IL-18 for IFN-γ gene expression: IL-12-induced STAT4 contributes to IFN-γ promoter activation by up-regulating the binding activity of IL-18-induced activator protein 1. J. Immunol.168(3), 1146–1153 (2002).
   PubMed Web of Science ®Google Scholar
• Luo C, Laaja P. Inhibitors of JAKs/STATs and the kinases: a possible new cluster of drugs. Drug Discov. Today9(6), 268–275 (2004).
   PubMed Web of Science ®Google Scholar
• Cetkovic-Cvrlje M, Uckun FM. Targeting Janus kinase 3 in the treatment of leukemia and inflammatory diseases. Arch. Immunol. Ther. Exp. (Warsz.)52(2), 69–82 (2004).
   PubMedGoogle Scholar
• O’Shea JJ, Pesu M, Borie DC, Changelian PS. A new modality for immunosuppression: targeting JAK/STAT pathway. Nat. Rev. Drug Discov.3(7), 555–564 (2004).
   PubMed Web of Science ®Google Scholar
• Vassilev AO, Tibbles HE, DuMez D, Venkatachalam TK, Uckun FM. Targeting JAK3 and BTK tyrosine kinases with rationally-designed inhibitors. Curr. Drug Targets7(3), 327–343 (2006).
   PubMedGoogle Scholar
• Sudbeck EA, Liu XP, Narla RK et al. Structure-based design of specific inhibitors of Janus kinase 3 as apoptosis-inducing antileukemic agents. Clin. Cancer Res.5(6), 1569–1582 (1999).
   PubMed Web of Science ®Google Scholar
• Stepkowski SM, Erwin-Cohen RA, Behbod F et al. Selective inhibitor of Janus tyrosine kinase 3, PNU156804, prolongs allograft survival and acts synergistically with cyclosporine but additively with rapamycin. Blood99(2), 680–389 (2002).
   PubMed Web of Science ®Google Scholar
• Wang LH, Kirken RA, Erwin RA, Yu CR, Farrar WL. JAK3, STAT, and MAPK signaling pathways as novel molecular targets for the tyrphostin AG-490 regulation of IL-2-mediated T cell response. J. Immunol.162(7), 3897–3904 (1999).
   PubMed Web of Science ®Google Scholar
• Pardanani A, Hood J, Lasho T et al. TG101209, a small molecule JAK2-selective kinase inhibitor potently inhibits myeloproliferative disorder-associated JAK2V617F and MPLW515L/K mutations. Leukemia21(8), 1658–1668 (2007).
   PubMed Web of Science ®Google Scholar
• Changelian PS, Flanagan ME, Ball DJ et al. Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Science302(5646), 875–878 (2003).
   PubMed Web of Science ®Google Scholar
• Stepkowski SM, Kao J, Wang ME et al. The Mannich base NC1153 promotes long-term allograft survival and spares the recipient from multiple toxicities. J. Immunol.175(7), 4236–4246 (2005).
   PubMed Web of Science ®Google Scholar
• Chen JJ, Thakur KD, Clark MP et al. Development of pyrimidine-based inhibitors of Janus tyrosine kinase 3. Bioorg. Med. Chem. Lett.16(21), 5633–5638 (2006).
   PubMedGoogle Scholar
• Clark George KM, Bookland RG et al. Development of new pyrrolopyrimidine-based inhibitors of Janus kinase 3 (JAK3). Bioorg. Med. Chem. Lett.17(5), 1250–1253 (2007).
   PubMedGoogle Scholar
• Cetkovic-Cvrlje M, Dragt AL, Vassilev A et al. Targeting JAK3 with JANEX-1 for prevention of autoimmune Type 1 diabetes in NOD mice. Clin. Immunol.106(3), 213–225 (2003).
   PubMed Web of Science ®Google Scholar
• Hampton T. Arthritis clinical trial results revealed. JAMA297(1), 28–29 (2007).
   PubMedGoogle Scholar
• Chan G, Wang C, Boy M, Chow V, Herron J. Dose-dependent reduction in psoriasis severity as evidence of immunosuppressive activity of an oral JAK3 inhibitor in humans. Am. J. Transplant.6(Suppl. 2), 87 (2006) (Abstract 60).
   Google Scholar
• Waetzig GH, Seegert D, Rosenstiel P, Nikolaus S, Schreiber S. p38 mitogen-activated protein kinase is activated and linked to TNF-α signaling in inflammatory bowel disease. J. Immunol.168(10), 5342–5351 (2002).
   PubMed Web of Science ®Google Scholar
• Revesz L, Blum E, Di Padova FE et al. Novel p38 inhibitors with potent oral efficacy in several models of rheumatoid arthritis. Bioorg. Med. Chem. Lett.14(13), 3595–3599 (2004).
   PubMedGoogle Scholar
• Westra J, Limburg PC, de Boer P, van Rijswijk MH. Effects of RWJ 67657, a p38 mitogen activated protein kinase (MAPK) inhibitor, on the production of inflammatory mediators by rheumatoid synovial fibroblasts. Ann. Rheum. Dis.63(11), 1453–1459 (2004).
   PubMed Web of Science ®Google Scholar
• Westra J, Doornbos-van der Meer B, de Boer P, van Leeuwen MA, van Rijswijk MH, Limburg PC. Strong inhibition of TNF-α production and inhibition of IL-8 and COX-2 mRNA expression in monocyte-derived macrophages by RWJ 67657, a p38 mitogen-activated protein kinase (MAPK) inhibitor. Arthritis Res. Ther.6(4), 384–392 (2004).
   PubMed Web of Science ®Google Scholar
• Miwatashi S, Arikawa Y, Kotani E et al. Novel inhibitor of p38 MAP kinase as an anti-TNF-α drug: discovery of N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (TAK-715) as a potent and orally active anti-rheumatoid arthritis agent. J. Med. Chem.48(19), 5966–5979 (2005).
   PubMed Web of Science ®Google Scholar
• Lin TH, Metzger A, Diller DJ et al. Discovery and characterization of triaminotriazine aniline amides as highly selective p38 kinase inhibitors. J. Pharmacol. Exp. Ther.318(2) 495–502 (2006).
   PubMed Web of Science ®Google Scholar
• Nikas SN, Drosos AA. SCIO-469 Scios Inc. Curr. Opin. Investig. Drugs5(11), 1205–1212 (2004).
   PubMedGoogle Scholar