Anti-inflammatory effects and joint protection in collagen-induced arthritis after treatment with IQ-1S, a selective c-Jun n-terminal kinase inhibitor

Journal of Pharmacology and Experimental Therapeutics

Volumn 353, Issue 3, 2015, Pages 505-516

  Schepetkin, Igor A ^a   Kirpotina, Liliya N ^a   Hammaker, Deepa ^b   Kochetkova, Irina ^a   Khlebnikov, Andrei I ^c,d   Lyakhov, Sergey A ^e   Firestein, Gary S ^b   Quinn, Mark T ^a  

^a MONTANA STATE UNIVERSITY   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c ALTAI STATE TECHNICAL UNIVERSITY   (Russian Federation)

^d NATIONAL RESEARCH TOMSK POLYTECHNIC UNIVERSITY   (Russian Federation)

^e A V BOGATSKY PHYSICO CHEMICAL INSTITUTE   (Ukraine)

Author keywords

[No Author keywords available]

Indexed keywords

11H INDENO[1,2 B]QUINOXALIN 11 ONE; 11H INDENO[1,2 B]QUINOXALIN 11 ONE OXIME; ANTHRA[1,9 CD]PYRAZOL 6(2H) ONE; INTERLEUKIN 1BETA; INTERSTITIAL COLLAGENASE; KETONE DERIVATIVE; STRESS ACTIVATED PROTEIN KINASE INHIBITOR; STROMELYSIN; UNCLASSIFIED DRUG; 11H-INDENO(1,2-B)QUINOXALIN-11-ONE OXIME; ANTIBODY; CYTOKINE; MATRIX METALLOPROTEINASE; OXIME; PROTEIN KINASE INHIBITOR; QUINOXALINE DERIVATIVE; STRESS ACTIVATED PROTEIN KINASE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIBODY TITER; ANTIINFLAMMATORY ACTIVITY; ARTICLE; COLLAGEN-INDUCED ARTHRITIS; CONTROLLED STUDY; FIBROBLAST; FOXP3+ CD4+ CD25+ REGULATORY T LYMPHOCYTE; GENE EXPRESSION; HUMAN; HUMAN CELL; IN VITRO STUDY; LYMPH NODE CELL; MALE; MMP1 GENE; MMP3 GENE; MOLECULAR DOCKING; MOUSE; NONHUMAN; PH; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; SYNOVIOCYTE; ANIMAL; ANTAGONISTS AND INHIBITORS; ARTHRITIS, EXPERIMENTAL; BINDING SITE; BIOSYNTHESIS; C57BL MOUSE; CHEMICAL STRUCTURE; CYTOLOGY; DOSE RESPONSE; DRUG EFFECTS; IMMUNOLOGY; JOINT; METABOLISM; PATHOLOGY; SYNOVIAL FLUID;

ANIMALS; ANTIBODIES; ARTHRITIS, EXPERIMENTAL; BINDING SITES; CYTOKINES; DOSE-RESPONSE RELATIONSHIP, DRUG; JNK MITOGEN-ACTIVATED PROTEIN KINASES; JOINTS; MALE; MATRIX METALLOPROTEINASES; MICE; MICE, INBRED C57BL; MODELS, MOLECULAR; OXIMES; PROTEIN KINASE INHIBITORS; QUINOXALINES; SYNOVIAL FLUID; T-LYMPHOCYTES, REGULATORY;

EID: 84939570393     PISSN: 00223565     EISSN: 15210103     Source Type: Journal    
DOI: 10.1124/jpet.114.220251     Document Type: Article

References (94)

1. Albert AS and Serjeant EP (1984) Determination of ionization constants by spectrophotometry, in The Determination of Ionization Constants, pp 70-101, Springer, Dordrecht, The Netherlands.
2. Alvaro-Gracia J.M., Zvaifler NJ, and Firestein GS (1990) Cytokines in chronic inflammatory arthritis. V. Mutual antagonism between interferon-gamma and tumor necrosis factor-alpha on HLA-DR expression, proliferation, collagenase production, and granulocyte macrophage colony-stimulating factor production by rheumatoid arthritis synoviocytes. J Clin Invest 86:1790-1798.
3. Armuzzi A, Lionetti P, Blandizzi C., Caporali R, Chimenti S, Cimino L., Gionchetti P, Girolomoni G, Lapadula G., Marchesoni A, et al. (2014) Anti-TNF agents as therapeutic choice in immune-mediated inflammatory diseases: focus on adalimumab. Int J Immunopathol Pharmacol 27 (Suppl)11-32.
4. Arnett FC, Edworthy SM, Bloch D.A., McShane DJ, Fries JF, Cooper NS, Healey L.A., Kaplan SR, Liang MH, Luthra HS, et al (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315-324.
5. Azizi G, Jadidi-Niaragh F, and Mirshafiey A (2013) Th17 cells in immunopathogenesis and treatment of rheumatoid arthritis. Int J Rheum Dis 16:243-253.
6. Bain J, McLauchlan H, Elliott M., and Cohen P (2003) The specificities of protein kinase inhibitors: an update. Biochem J 371:199-204.
7. Bartok B and Firestein GS (2010) Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev 233:233-255.
8. Bernotiene E, Palmer G, Talabot-Ayer D, Szalay-Quinodoz I, Aubert ML, and Gabay C (2004) Delayed resolution of acute inflammation during zymosan-induced arthritis in leptin-deficient mice. Arthritis Res Ther 6:R256-R263.
9. Bhagwat SS (2007) MAP kinase inhibitors in inflammation and autoimmune disorders. Annu Rep Med Chem 42:265-278.
10. Bogoyevitch MA, Boehm I, Oakley A., Ketterman AJ, and Barr RK (2004) Targeting the JNK MAPK cascade for inhibition: basic science and therapeutic potential. Biochim Biophys Acta 1697:89-101.
11. Bogoyevitch MA, Ngoei KR, Zhao T.T., Yeap YY, and Ng DC (2010) c-Jun N-terminal kinase (JNK) signaling: recent advances and challenges. Biochim Biophys Acta 1804:463-475.
12. Brand DD, Kang AH, and Rosloniec EF (2003) Immunopathogenesis of collagen arthritis. Springer Semin Immunopathol 25:3-18.
13. Burrage PS, Mix KS, and Brinckerhoff CE (2006) Matrix metalloproteinases: role in arthritis. Front Biosci 11:529-543.
14. Campbell DJ and Ziegler SF (2007) FOXP3 modifies the phenotypic and functional properties of regulatory T cells. Nat Rev Immunol 7:305-310.
15. Cao Y, Takada E, Hata K., Sudo K, Furuhata M, and Mizuguchi J (2010) Enhanced T cell-independent antibody responses in c-Jun N-terminal kinase 2 (JNK2)-deficient B cells following stimulation with CpG-1826 and anti-IgM. Immunol Lett 132:38-44.
16. Carranza F, Falcón CR, Nuñez N, Knubel C., Correa SG, Bianco I, Maccioni M, Fretes R., Triquell MF, Motrán CC, et al. (2012) Helminth antigens enable CpG-activated dendritic cells to inhibit the symptoms of collagen-induced arthritis through Foxp3+ regulatory T cells. PLoS ONE 7:e40356.
17. Chen L, Wu J, Ren W., Yang X, and Shen Z (2013) c-Jun N-terminal kinase (JNK)-phospho-c-JUN (ser63/73) pathway is essential for FOXP3 nuclear translocation in psoriasis. J Dermatol Sci 69:114-121.
18. Coffey G, DeGuzman F, Inagaki M., Pak Y, Delaney SM, Ives D, Betz A., Jia ZJ, Pandey A, Baker D, et al (2012) Specific inhibition of spleen tyrosine kinase suppresses leukocyte immune function and inflammation in animal models of rheumatoid arthritis. J Pharmacol Exp Ther 340:350-359.
19. Cohen S and Fleischmann R (2010) Kinase inhibitors: a new approach to rheumatoid arthritis treatment. Curr Opin Rheumatol 22:330-335.
20. Cros J, Thibault A, and Dat-Xuong N (1975) [Anti-inflammatory effect of hydroxy-9-ellipticine]. C R Acad Sci Hebd Seances Acad Sci D 281:1139-1142.
21. Cuzzocrea S, Mazzon E, Di Paola R, Muià C, Crisafulli C, Dugo L, Collin M, Britti D, Caputi AP, and Thiemermann C (2006) Glycogen synthase kinase-3beta inhibition attenuates the degree of arthritis caused by type II collagen in the mouse. Clin Immunol 120:57-67.
22. Davignon JL, Hayder M, Baron M., Boyer JF, Constantin A, Apparailly F, Poupot R., and Cantagrel A (2013) Targeting monocytes/macrophages in the treatment of rheumatoid arthritis. Rheumatology (Oxford) 52:590-598.
23. Deady LW, Kaye AJ, Finlay G.J., Baguley BC, and Denny WA (1997) Synthesis and antitumor properties of N-[2-(dimethylamino)ethyl]carboxamide derivatives of fused tetracyclic quinolines and quinoxalines: a new class of putative topoisomerase inhibitors. J Med Chem 40:2040-2046.
24. Dehlin M, Andersson S, Erlandsson M., Brisslert M, and Bokarewa M (2011) Inhibition of fms-like tyrosine kinase 3 alleviates experimental arthritis by reducing formation of dendritic cells and antigen presentation. J Leukoc Biol 90:811-817.
25. Dérijard B., Hibi M, Wu I.H., Barrett T., Su B, Deng T, Karin M., and Davis RJ (1994) JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell 76:1025-1037.
26. Drexler SK, Kong PL, Wales J, and Foxwell BM (2008) Cell signalling in macrophages, the principal innate immune effector cells of rheumatoid arthritis. Arthritis Res Ther 10:216.
27. Fabian MA, Biggs WH, 3rd, Treiber DK, Atteridge CE, Azimioara MD, Benedetti MG, Carter TA, Ciceri P, Edeen PT, Floyd M, et al. (2005) A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 23:329-336.
28. Firestein GS (2003) Evolving concepts of rheumatoid arthritis. Nature 423:356-361.
29. Gao B, Calhoun K, and Fang D (2006) The proinflammatory cytokines IL-1beta and TNF-alpha induce the expression of Synoviolin, an E3 ubiquitin ligase, in mouse synovial fibroblasts via the Erk1/2-ETS1 pathway. Arthritis Res Ther 8:R172.
30. Ghalib RM, Hashim R, Sulaiman O., Hemamalini M, and Fun HK (2010) 11H-Indeno-[1,2-b]quinoxalin-11-one. Acta Crystallogr Sect E Struct Rep Online 66:o1494.
31. Guma M and Firestein GS (2012) c-Jun N-terminal kinase in inflammation and rheumatic diseases. Open Rheumatol J 6:220-231.
32. Guma M, Kashiwakura J, Crain B., Kawakami Y, Beutler B, Firestein G.S., Kawakami T., Karin M, and Corr M (2010) JNK1 controls mast cell degranulation and IL-1beta production in inflammatory arthritis. Proc Natl Acad Sci USA 107:22122-22127.
33. Guma M, Ronacher LM, Firestein G.S., Karin M., and Corr M (2011) JNK-1 deficiency limits macrophage-mediated antigen-induced arthritis. Arthritis Rheum 63: 1603-1612.
34. Gupta S, Barrett T, Whitmarsh A.J., Cavanagh J., Sluss HK, Dérijard B, and Davis RJ (1996) Selective interaction of JNK protein kinase isoforms with transcription factors. EMBO J 15:2760-2770.
35. Han H, Lee KS, Rong W, and Zhang G (2012) Different roles of peripheral mitogen-activated protein kinases in carrageenan-induced arthritic pain and arthritis in rats. Anesth Analg 115:1221-1227.
36. Han Z, Boyle DL, Aupperle K.R., Bennett B., Manning AM, and Firestein GS (1999) Jun N-terminal kinase in rheumatoid arthritis. J Pharmacol Exp Ther 291:124-130.
37. Han Z, Boyle DL, Chang L, Bennett B., Karin M, Yang L, Manning A.M., and Firestein GS (2001) c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J Clin Invest 108:73-81.
38. Harbecke O, Dahlgren C, Bergman J., and Möller L (1999) The synthetic non-toxic drug 2,3-dimethyl-6(2-dimethylaminoethyl)-6H-indolo-(2,3-b)quinoxaline inhibits neutrophil production of reactive oxygen species. J Leukoc Biol 65:771-777.
39. Hegen M, Keith JC, Jr, Collins M, and Nickerson-Nutter CL (2008) Utility of animal models for identification of potential therapeutics for rheumatoid arthritis. Ann Rheum Dis 67:1505-1515.
40. Heo YS, Kim SK, Seo C.I., Kim YK, Sung BJ, Lee HS, Lee J.I., Park SY, Kim JH, Hwang KY, et al (2004) Structural basis for the selective inhibition of JNK1 by the scaffolding protein JIP1 and SP600125. EMBO J 23:2185-2195.
41. Hultqvist M, Nandakumar KS, Björklund U, and Holmdahl R (2009) The novel small molecule drug Rabeximod is effective in reducing disease severity of mouse models of autoimmune disorders. Ann Rheum Dis 68:130-135.
42. Inoue T, Hammaker D, Boyle D.L., and Firestein GS (2005) Regulation of p38 MAPK by MAPK kinases 3 and 6 in fibroblast-like synoviocytes. J Immunol 174:4301-4306.
43. Inoue T, Hammaker D, Boyle D.L., and Firestein GS (2006) Regulation of JNK by MKK-7 in fibroblast-like synoviocytes. Arthritis Rheum 54:2127-2135.
44. Joetham A, Ohnishi H, Okamoto M., Takeda K, Schedel M, Domenico J., Dakhama A, and Gelfand EW (2012) Loss of T regulatory cell suppression following signaling through glucocorticoid-induced tumor necrosis receptor (GITR) is dependent on c-Jun N-terminal kinase activation. J Biol Chem 287:17100-17108.
45. Karaman MW, Herrgard S, Treiber D.K., Gallant P., Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis M.I., Edeen PT, et al. (2008) A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol 26:127-132.
46. Karin M and Gallagher E (2005) From JNK to pay dirt: jun kinases, their biochemistry, physiology and clinical importance. IUBMB Life 57:283-295.
47. Khan MS, Munawar MA, Ashraf M, Alam U., Ata A, Asiri AM, Kousar S, and Khan MA (2014) Synthesis of novel indenoquinoxaline derivatives as potent α-glucosi-dase inhibitors. Bioorg Med Chem 22:1195-1200.
48. Kinne RW, Bräuer R, Stuhlmüller B, Palombo-Kinne E, and Burmester GR (2000) Macrophages in rheumatoid arthritis. Arthritis Res 2:189-202.
49. Koch P, Gehringer M, and Laufer SA (2015) Inhibitors of c-Jun N-terminal kinases: an update. J Med Chem 58:72-95.
50. + regulatory T cells confers protection against collagen II-induced arthritis via the production of IL-10. J Immunol 184:7144-7153.
51. Kochetkova I, Thornburg T, Callis G., Holderness K, Maddaloni M, and Pascual DW (2014) Oral Escherichia coli colonization factor antigen I fimbriae ameliorate arthritis via IL-35, not IL-27. J Immunol 192:804-816.
52. Kochetkova I, Trunkle T, Callis G., and Pascual DW (2008) Vaccination without autoantigen protects against collagen II-induced arthritis via immune deviation and regulatory T cells. J Immunol 181:2741-2752.
53. Köller M., Hayer S, Redlich K., Ricci R, David JP, Steiner G, Smolen J.S., Wagner EF, and Schett G (2005) JNK1 is not essential for TNF-mediated joint disease. Arthritis Res Ther 7:R166-R173.
54. Kyttaris VC (2012) Kinase inhibitors: a new class of antirheumatic drugs. Drug Des Devel Ther 6:245-250.
55. Lee E, Jeong KW, Shin A, Jin B., Jnawali HN, Jun BH, Lee JY, Heo Y.S., and Kim Y (2013) Binding model for eriodictyol to Jun-N terminal kinase and its antiinflammatory signaling pathway. BMB Rep 46:594-599.
56. Lee SI, Boyle DL, Berdeja A, and Firestein GS (2012) Regulation of inflammatory arthritis by the upstream kinase mitogen activated protein kinase kinase 7 in the c-Jun N-terminal kinase pathway. Arthritis Res Ther 14:R38.
57. Lehmann J, Huehn J, de la Rosa M, Maszyna F, Kretschmer U, Krenn V, Brunner M, Scheffold A, and Hamann A (2002) Expression of the integrin alpha Ebeta 7 identifies unique subsets of CD25+ as well as CD25- regulatory T cells. Proc Natl Acad Sci USA 99:13031-13036.
58. Li J, Hsu HC, and Mountz JD (2012) Managing macrophages in rheumatoid arthritis by reform or removal. Curr Rheumatol Rep 14:445-454.
59. Liacini A, Sylvester J, Li W.Q., and Zafarullah M (2002) Inhibition of interleukin-1-stimulated MAP kinases, activating protein-1 (AP-1) and nuclear factor kappa B (NF-kappa B) transcription factors down-regulates matrix metalloproteinase gene expression in articular chondrocytes. Matrix Biol 21:251-262.
60. Manning AM and Davis RJ (2003) Targeting JNK for therapeutic benefit: from junk to gold? Nat Rev Drug Discov 2:554-565.
61. McIntyre KW, Shuster DJ, Gillooly K.M., Dambach DM, Pattoli MA, Lu P, Zhou X.D., Qiu Y., Zusi FC, and Burke JR (2003) A highly selective inhibitor of I kappa B kinase, BMS-345541, blocks both joint inflammation and destruction in collageninduced arthritis in mice. Arthritis Rheum 48:2652-2659.
62. Mehan S, Meena H, Sharma D., and Sankhla R (2011) JNK: a stress-activated protein kinase therapeutic strategies and involvement in Alzheimer's and various neurodegenerative abnormalities. J Mol Neurosci 43:376-390.
63. Meier FM and McInnes IB (2014) Small-molecule therapeutics in rheumatoid arthritis: scientific rationale, efficacy and safety. Best Pract Res Clin Rheumatol 28: 605-624.
64. Moorthy NSHN, Manivannan E, Karthikeyan C., and Trivedi P (2013) 6H-Indolo[2,3-b]quinoxalines: DNA and protein interacting scaffold for pharmacological activities. Mini Rev Med Chem 13:1415-1420.
65. Myers LK, Rosloniec EF, Cremer M.A., and Kang AH (1997) Collagen-induced arthritis, an animal model of autoimmunity. Life Sci 61:1861-1878.
66. Nakae S, Nambu A, Sudo K., and Iwakura Y (2003) Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J Immunol 171: 6173-6177.
67. Nandakumar KS, Andrén M, Martinsson P., Bajtner E, Hellström S, Holmdahl R., and Kleinau S (2003) Induction of arthritis by single monoclonal IgG anti-collagen type II antibodies and enhancement of arthritis in mice lacking inhibitory FcgammaRIIB. Eur J Immunol 33:2269-2277.
68. Nishikawa M, Myoui A, Tomita T., Takahi K, Nampei A, and Yoshikawa H (2003) Prevention of the onset and progression of collagen-induced arthritis in rats by the potent p38 mitogen-activated protein kinase inhibitor FR167653. Arthritis Rheum 48:2670-2681.
69. Ogata M, Matsumoto H, Shimizu S., Kida S, Wada T, Shiro M., and Sato K (1986) Synthesis and antiviral activity of sulfonamidobenzophenone oximes and sulfonamidobenzamides. J Med Chem 29:417-423.
70. Ohori M, Takeuchi M, Maruki R., Nakajima H, and Miyake H (2007) FR180204, a novel and selective inhibitor of extracellular signal-regulated kinase, ameliorates collagen-induced arthritis in mice. Naunyn Schmiedebergs Arch Pharmacol 374: 311-316.
71. Pesu M, Laurence A, Kishore N., Zwillich SH, Chan G, and O'Shea JJ (2008) Therapeutic targeting of Janus kinases. Immunol Rev 223:132-142.
72. Podolin PL, Callahan JF, Bolognese B.J., Li YH, Carlson K, Davis TG, Mellor G.W., Evans C., and Roshak AK (2005) Attenuation of murine collagen-induced arthritis by a novel, potent, selective small molecule inhibitor of IkappaB kinase 2, TPCA-1 (2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide), occurs via reduction of proinflammatory cytokines and antigen-induced T cell proliferation. J Pharmacol Exp Ther 312:373-381.
73. Prince HE (2005) Biomarkers for diagnosing and monitoring autoimmune diseases. Biomarkers 10 (Suppl 1):S44-S49.
74. Rincón M and Davis RJ (2009) Regulation of the immune response by stress-activated protein kinases. Immunol Rev 228:212-224.
75. Rincón M and Pedraza-Alva G (2003) JNK and p38 MAP kinases in CD4+ and CD8+ T cells. Immunol Rev 192:131-142.
76. Rosengren S, Corr M, Firestein G.S., and Boyle DL (2012) The JAK inhibitor CP-690,550 (tofacitinib) inhibits TNF-induced chemokine expression in fibroblast-like synoviocytes: autocrine role of type I interferon. Ann Rheum Dis 71:440-447.
77. Schepetkin IA, Kirpotina LN, Khlebnikov A.I., Hanks TS, Kochetkova I, Pascual DW, Jutila M.A., and Quinn MT (2012) Identification and characterization of a novel class of c-Jun N-terminal kinase inhibitors. Mol Pharmacol 81:832-845.
78. Schramm C, Kriegsmann J, Protschka M., Huber S, Hansen T, Schmitt E., Galle PR, and Blessing M (2004) Susceptibility to collagen-induced arthritis is modulated by TGFbeta responsiveness of T cells. Arthritis Res Ther 6:R114-R119.
79. Schurgers E, Billiau A, and Matthys P (2011) Collagen-induced arthritis as an animal model for rheumatoid arthritis: focus on interferon-g. J Interferon Cytokine Res 31:917-926.
80. Stevens TL, Bossie A, Sanders V.M., Fernandez-Botran R, Coffman RL, Mosmann T.R., and Vitetta ES (1988) Regulation of antibody isotype secretion by subsets of antigen-specific helper T cells. Nature 334:255-258.
81. Sundarrajan M, Boyle DL, Chabaud-Riou M, Hammaker D., and Firestein GS (2003) Expression of the MAPK kinases MKK-4 and MKK-7 in rheumatoid arthritis and their role as key regulators of JNK. Arthritis Rheum 48:2450-2460.
82. Tak PP and Bresnihan B (2000) The pathogenesis and prevention of joint damage in rheumatoid arthritis: advances from synovial biopsy and tissue analysis. Arthritis Rheum 43:2619-2633.
83. Thalhamer T, McGrath MA, and Harnett MM (2008) MAPKs and their relevance to arthritis and inflammation. Rheumatology (Oxford) 47:409-414.
84. Tissi L, Bistoni F, and Puliti M (2009) IL-4 deficiency decreases mortality but increases severity of arthritis in experimental group B Streptococcus infection. Mediators Inflamm 2009:394021.
85. Toyama S, Tamura N, Haruta K., Karakida T, Mori S, Watanabe T., Yamori T, and Takasaki Y (2010) Inhibitory effects of ZSTK474, a novel phosphoinositide 3-kinase inhibitor, on osteoclasts and collagen-induced arthritis in mice. Arthritis Res Ther 12:R92.
86. Triantaphyllopoulos K, Madden L, Rioja I., Essex D, Buckton J, Malhotra R., Ray K, Binks M, and Paleolog EM (2010) In vitro target validation and in vivo efficacy of p38 MAP kinase inhibition in established chronic collagen-induced arthritis model: a pre-clinical study. Clin Exp Rheumatol 28:176-185.
87. van den Broek LAGM, Kat-Van Den Nieuwenhof MW, Butters TD, and Van Boeckel CA (1996) Synthesis of alpha-glucosidase I inhibitors showing antiviral (HIV-1) and immunosuppressive activity. J Pharm Pharmacol 48:172-178.
88. van Leeuwen M.A., Westra J, Limburg P.C., van Riel PL, and van Rijswijk MH (1995) Interleukin-6 in relation to other proinflammatory cytokines, chemotactic activity and neutrophil activation in rheumatoid synovial fluid. Ann Rheum Dis 54:33-38.
89. Vinh NB, Simpson JS, Scammells P.J., and Chalmers DK (2012) Virtual screening using a conformationally flexible target protein: models for ligand binding to p38a MAPK. J Comput Aided Mol Des 26:409-423.
90. Wachstein J, Tischer S, Figueiredo C., Limbourg A, Falk C, Immenschuh S., Blasczyk R, and Eiz-Vesper B (2012) HSP70 enhances immunosuppressive function of CD4 (+)CD25(+)FoxP3(+) T regulatory cells and cytotoxicity in CD4(+)CD25(-) T cells. PLoS ONE 7:e51747.
91. Wang T, Arifoglu P, Ronai Z., and Tew KD (2001) Glutathione S-transferase P1-1 (GSTP1-1) inhibits c-Jun N-terminal kinase (JNK1) signaling through interaction with the C terminus. J Biol Chem 276:20999-21003.
92. Willenborg DO, Parish CR, and Cowden WB (1992) Inhibition of adjuvant arthritis in the rat by phosphosugars and the alpha-glucosidase inhibitor castanospermine. Immunol Cell Biol 70:369-377.
93. Xu D, Kim Y, Postelnek J., Vu MD, Hu DQ, Liao C, Bradshaw M., Hsu J, Zhang J, Pashine A., et al. (2012) RN486, a selective Bruton's tyrosine kinase inhibitor, abrogates immune hypersensitivity responses and arthritis in rodents. J Pharmacol Exp Ther 341:90-103.
94. Zhou CL, Lu R, Lin G., and Yao Z (2011) The latest developments in synthetic peptides with immunoregulatory activities. Peptides 32:408-414.