Suppressors of cytokine signaling (SOCS): Inhibitors of the JAK/STAT pathway

Shock

Volumn 17, Issue 2, 2002, Pages 83-90

  Cooney, Robert N ^a  

^a PENN STATE COLLEGE OF MEDICINE   (United States)

Author keywords

Cytokines; Erythropoietin; Growth hormone; IFN ; Leptin

Indexed keywords

CARRIER PROTEIN; CYTOKINE; DNA BINDING PROTEIN; JAK1 PROTEIN, HUMAN; JANUS KINASE 1; PROTEIN; PROTEIN TYROSINE KINASE; REPRESSOR PROTEIN; SIGNAL PEPTIDE; SOCS1 PROTEIN, HUMAN; SOCS5 PROTEIN, HUMAN; STAT1 PROTEIN; STAT1 PROTEIN, HUMAN; SUPPRESSOR OF CYTOKINE SIGNALING; TRANSACTIVATOR PROTEIN;

ANIMAL; GENETICS; HUMAN; METABOLISM; MOLECULAR CLONING; MULTIGENE FAMILY; PHYSIOLOGY; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; CARRIER PROTEINS; CLONING, MOLECULAR; CYTOKINES; DNA-BINDING PROTEINS; HUMANS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; JANUS KINASE 1; MULTIGENE FAMILY; PROTEIN-TYROSINE KINASES; PROTEINS; REPRESSOR PROTEINS; SIGNAL TRANSDUCTION; STAT1 TRANSCRIPTION FACTOR; SUPPRESSOR OF CYTOKINE SIGNALING PROTEINS; TRANS-ACTIVATORS;

EID: 0036480027     PISSN: 10732322     EISSN: None     Source Type: Journal    
DOI: 10.1097/00024382-200202000-00001     Document Type: Review

References (93)

1. Ihle JN: Cytokine receptor signaling. Nature 377:591-594, 1995.
2. Ihle JN: STATs: signal transducers and activators of transcription. Cell 84:331-334, 1996.
3. Leonard WJ, O'Shea JJ: Jaks and STATs: biological implications. Annu Rev Immunol. 16:293-322, 1998.
4. Imada K, Leonard WJ: The JAK-STAT pathway. Mol Immunol 37:1-11, 2000.
5. Aringer M, Cheng A, Nelson JW, Chen M, Sudarshan C, Zhou YJ, O'Shea JJ: Janus kinases and their role in growth and disease. Life Sci 64:2173-2186, 1999.
6. Weiss A, Schlessinger J: Switching signals on or off by receptor dimerization. Cell 94:277-280, 1998.
7. Shuai K. Modulation of STAT signaling by STAT-interacting proteins. Oncogene 19:2638-2644, 2000.
8. Argetsinger LS, Campbell GS, Yang X, Witthuhn BA, Silvennoinen O, Ihle JN, Carter-Su C: Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase. Cell 74:237-244, 1993.
9. Vinkemeier U, Moarefi I, Darnell JE, Kuriyan J: Structure of the amino-terminal protein interaction domain of STAT-4. Science 279:1048-1052, 1998.
10. Soldaini E, John S, Moro S, Bollenbacher J, Schindler U, Leonard WJ: DNA-binding site selection of dimeric and tetrameric StatS proteins reveals a large repertoire of divergent tetrameric Stat5a-binding sites. Mol Cell Biol 20:389-401, 2000.
11. Smit LS, Meyer DJ, Billestrup N, Norstedt G, Schwartz J, Carter-Su C: The role of the growth hormone (GH) receptor and JAK1 and JAK2 kinases in the activation of Stats 1, 3, and 5 by GH. Mol Endocrinol 10:519-533, 1996.
12. Campbell GS, Meyer DJ, Raz R, Levy DE, Schwartz J, Carter-Su C: Activation of acute phase response factor (APFR)/Stat3 transcription factor by growth hormone. J Biol Chem 270:3974-3979, 1997.
13. Smit LS, Vanderkuur JA, Stimage A, Han YL, Luo GY, Yulee LY, Schwartz J, Carter-Su C: Growth hormone induced tyrosyl phosphorylation and deoxyribonucleic acid binding activity of Stat5A and Stat5B. Endocrinology 138: 3426-3434, 1997.
14. Boisclair YR, Wang J, Shi J, Hurst KR, Ooi GT: Role of the suppressor of cytokine signling-3 in mediating the inhibitory effects of interleukin-1β on the growth-hormone-dependent transcription of the acid labile subunit gene in lever cells. J Biol Chem 275:3841-3847, 2000.
15. Bergad PL, Schwarzenberg SJ, Humbert JT, Morrison M, Amarasinghe S, Towle HC, Berry SA: Inhibition of growth hormone action in models of inflammation. Am J Physiol Cell Physiol 279:C1906-C1917, 2000.
16. Davey HW, McLachlan MJ, Wilkins RJ, Hilton DJ, Adams TE: STAT5b mediates the GH-induced expression of SOCS-2 and SOCS-3 mRNA in the liver. Mol Cell Endocrinol 158:111-116, 1999.
17. Adams TE, Hansen JA, Starr R, Nicola NA, Hilton DJ, Billestrup N: Growth hormone preferentially induces the rapid, transient expression of SOCS-3, a novel inhibitor of cytokine receptor signaling. J Bio. Chem 273:1285-1287, 1997.
18. Rodig S, Meraz MA, White JM, Lampe PA, Riley JK, Arthur CD, King KL, Sheehan KC, Yin L, Pennica D, Johnson EM, Schreiber RD: Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell 93:373-383, 1998.
19. Parganas E, Wang D, Stravopodis D, Topham DJ, Marine JC, Teglund S, Vanin E, Bodner S, Colamonici OR, van Deursen JM, Grosveld G, Ihle JN: Jak2 is essential for signaling through a variety of cytokine receptors. Cell 93:385-395, 1998.
20. Neubauer H, Cumano A, Muller M, Wu H, Huffstadt U, Pfeffer K: Jak2 deficiency defines an essential development checkpoint in definitive erythropoiesis. Cell 93:397-409, 1998.
21. Nosaka T, van Deursen JM, Tripp RA, Thierfelder WE, Witthuhn BA, McMickle AP, Doherty PC, Grosveld GC, Ihle JN: Defective lymphoid development in mice lacking Jak3. Science 270:800-802, 1995.
22. Cao X, Shores EW, Hu-Li J, Anver MR, Kelsall BL, Russell SM, Drago J, Noguchi M, Grinberg A, Bloom ET, Paul WE, Katz SI, Love PE, Leonard WJ: Defective lymphoid development in mice lacking expression of the common cytokine receptor y chain. Immunity 2:223-238, 1995.
23. DiSanto JP, Muller W, Guy-Grand D, Fischer A, Rajewsky K: Lymphoid development in mice with a targeted deletion of the interleukin-2 receptor γ chain. Proc Natl Acad Sci USA 92:377-381, 1995.
24. Meraz MA, White JM, Sheehan KC, Bach EA, Rodig SJ, Dighe AS, Kaplan DH, Riley JK, Greenlund AC, Campbell D, Carver-Moore K, DuBois RN, Clark R, Aguet M, Schreiber RD: Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell 84:431-442, 1996.
25. Takeda K, Noguchi K, Shi W, Tanaka T, Matsumoto M, Yoshida N, Kishimoto T, Akira S: Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc Natl Acad Sc USA 94:3801-3804, 1997.
26. Takeda K, Kaisho T, Yoshida N, Takeda J, Kishimoto T, Akira S: STAT3 activation is responsible for IL-6-dependent T-cell proliferation through preventing apoptosis: generation and characterization of T cell specific Stat3-deficient mice. J Immunol 161:4652-4660, 1998.
27. Takeda K, Clausen BE, Kaisho T, Tsujimura T, Terada N, Forster I, Akira S: Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 10:39-49, 1999.
28. Kaplan MH, Sun YL, Hoey T, Grusby MJ: Impaired IL-12 responses and enhanced development of Th2 cell in Stat4 deficient mice. Nature 382:174-177, 1996.
29. Mui AL, Wakao H, O'Farrell AM, Harda N, Miyajima A: Interleukin-3, granulocyte-macrophage colony stimulating factor and interleukin-5 transduce signals through two Stat5 homologs. EMBO J 14:1166-1175, 1995.
30. Liu X, Robinson GW, Wagner K, Garret L, Ulynshaw-Boris A, Hennighausen L: Stat5a is mandatory for adult mammary gland development and lactogenesis. Genes Dev 11:179-186, 1997.
31. Udy GB, Towers RP Snell RG, Wilkins RJ, Park SH, Ram PA, Waxman DJ, Davey HW: Requirement of Stat5b for sexual dimorphism of body growth rates and liver gene expression. Proc Natl Acad Sci USA 94:7239-7244, 1997.
32. Takeda K, Tanaka T, Shi W, Matsmoto M, Minami M, Kshiwamura S, Nakanishi K, Yoshida N, Kishmoto T, Akira S: Essential role of Stat6 in IL-4 signaling. Nature 380:627-630, 1996.
33. Kaplan MH, Schindler U, Smiley ST, Grusby MJ: Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity 4:313-319, 1996.
34. Strous GJ, van Kerkhof P, Govers R, Ciechanover A, Schwartz AL: The ubiquitin conjugation system is required for ligand-induced endocytosis and degradation of the growth hormone receptor. EMBO J 15:3806-3812, 1996.
35. Haque SJ, Harbor P, Tabrizi M, Yi T, Williams BR: Protein-tyrosine phosphatase Shp-1 is a negative regulator of IL-4 and IL-13-dependent signal transduction. J Biol Chem 273:33893-33896, 1998.
36. Jiao H, Berrada K, Yang W, Tabrizi M, Platanias LC, Yi T: Direct association with and dephosphorylation of Jak2 kinase by the SH2-domain-containing protein tyrosine phosphatase SHP-1. Mol Cell Biol 16:6985-6992, 1996.
37. Kim H, Hawley TS, Hawley RG, Baumann H: Protein tyrosine phosphatase 2 (SHP-2) moderates signaling by gp130 but is not required for the induction of the acute phase plasma protein genes in hepatic cells. Mol Cell Biol 18:1525-1533, 1998.
38. You M, Yu DH, Feng GS: Shp-2 tyrosine phosphatase functions as a negative regulator of the interferon-stimulated Jak/Stat pathway. Mol Cell Biol 19:2416-2424, 1999.
39. Chung CD, Liao J, Liu B, Rao X, Jay P, Berta P, Shuai K: Specific inhibition of Stat3 signal transduction by PIAS3. Science 278:1803-1805, 1997.
40. Liu, Liao J, Rao X, Kushner SA, Chung CD, Chang DD, Shuai K: Inhibition of Stat1 mediated gene activation by PIAS1. Proc Natl Acad Sci USA 95:10626-10631, 1998.
41. Nicholson SE, Hilton DJ: The SOCS proteins: a new family of negative regulators of signal transduction. J Leuk Biol 63:665-668, 1998.
42. Yoshimura A: The CIS/JAB family: novel negative regulators of JAK signaling pathways. Leukemia 12:1851-1857, 1998.
43. Yoshimura A, Ohkubo T, Kiguchi T, Jenkins NA, Gilbert DJ, Copelland NG, Hara T, Miyajima: A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors. EMBO J 14:2816-2826, 1995.
44. Starr R, Willson TA, Viney EM, Murray LJL, Rayner JR, Jenkins BJ, Gonda TJ, Alexander WS, Metcalf D, Nicola NA, Hilton DJ: A family of cytokine-inducible inhibitors of signaling. Nature 387:917-921, 1997.
45. Endo TA, Masuhara M, Yokouchi M, Suzuki R, Sakamoto H, Mitsui K, Matsumoto A, et al.: A new protein containing an SH2 domain that inhibits JAK kinases. Nature 387:921-924, 1997.
46. Naka T, Narazaki M, Hirata M, Matsumoto T, Minamoto S, et al.: Structure and function of a new family of STAT-induced STAT inhibitor. Nature 387:924-928, 1997.
47. Hilton DJ, Richardson RT, Alexander WS, Viney EM, Willson TA, Sprigg NS, Starr R, Nicholson SE, Metcalf D, Nicola NA: Twenty proteins containing a C-terminal SOCS box form five structural classes. Proc Natl Acad Sci USA 95:114-119, 1998.
48. Krebs DL, Hilton DJ: SOCS: physiologic suppressors of cytokine signaling. J Cell Sci 113:2813-2819, 2000.
49. Chen XP, Losman JA, Rothman P: SOCS proteins, regulators of intracellular signaling. Immunity 13:287-290, 2000.
50. Yasukawa H, Sasaki A, Yoshimura A: Negative regulation of cytokine signaling pathways. Annu Rev Immunol 18:143-164, 2000.
51. Narazaki M, Fujimoto M, Matsumoto T, Morita Y, Saito H, Kajita T, Yoshizaki K, Naka T, Kishimoto T: Three distinct domains of SSI/SOCS-1/JAB protein are required for its suppression of interleukin-6 signaling. Proc Natl Acad Sci USA 95:13130-13134, 1998.
52. Kamura T, Sato S, Haque D, Liu L, Kaelin WG, Conaway RC, Conaway JW: The elongin BC complex interacts with the conserved SOCS box motif present in members of the SOCS, ras, WD-4-repeat, and ankyrin repeat families. Genes Dev 12:3872-3881, 1998.
53. Zhang JG, Farley A, Nicholson SE, Willson TA, Zugaro LM, Simpson RJ, Moritz RL, Cary D, Richardson R, Hausmann G, et al.: The conserved SOCS box motif in suppressors of cyotokine signaling binds to elongins B and C and may couple bound proteins to proteasomal degradation. Proc Natl Acad Sci USA 96:2071-2076. 1999.
54. Kaelin WG, Maher ER: The VHL tumour-suppressor paradigm. Trends Genet 14:423-426, 1998.
55. Conaway JW, Kamura T, Conaway RC: The elongin BC complex and the von Hippel-Lindau tumor suppressor protein. Biochem Biophys Acta 1377:M49-M54, 1998.
56. Tollet-Egnell P, Flores-Morales A, Stavreus-Evers A, Sahlin L, Norstedt G: Growth hormone regulation of SOCS-2, SOCS-3, and CIS messenger ribonucleic acid expression in the rat. Endocrinology 140:3693-3704, 1999.
57. Matsumoto A, Masuhara M, Mitsui K, Yokouchi M, Ohtsubo M, Misawa H, Miyajima A, and Yoshimura A: CIS, a cytokine inducible SH2 protein is a target of the JAK-STAT pathway and modulates STAT5 activation. Blood 89:3148-3154, 1997.
58. Saito H, Morita Y, Fujimoto M, Narazaki M, Naka T, Kishimoto T: IFN Regulatory factor-1-mediated transcriptional activation of mouse STAT-induced STAT inhibitor-1 gene promoter by IFN-γ. J Immunol 164:5833-5843, 2000.
59. Teglund S, McKay C, Schuetz E, van Deursen JM, Stravapodis D, Wang D, Brown M, Bodner S, Grosveld G, Ihle JN: Stat5a and Stat5b proteins have essential and nonessential, or redundant roles in cytokine responses. Cell 93: 841-850, 1998.
60. Mui AL, Wakao H, Kinoshita T, Kitamura T, Miyajima A: Suppression of interleukin-3-induced gene expression by a C-terminal truncated Stat5: role of Stat5 in proliferation. EMBO J 15:2425-2433, 1996.
61. Gregorieff A, Pyronnet S, Sonenberg N, Veillette A: Regulation of SOCS-1 expression by translational repression. J Biol Chem 275:21596-21604, 2000.
62. Yasukawa H, Misawa H, Sakamoto H, Masuhara M, Sasaki A, Wakioka T, Ohtsuka S, Imaizumi T, Matsuda T, Ihle JN, Yoshimura A: The JAK binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop. EMBO J 18:1309-1320, 1999.
63. Pezet A, Favre H, Kelly PA, Edery M: Inhibition and restoration of prolactin signal transduction by suppressors of cytokine signaling. J Biol Chem 274: 24497-24502, 1999.
64. Masuhara M, Sakamoto H, Matsumoto A, Suzuki R, Yasukawa H, Mitsui K, Wakioka T, Tanimura S, Sasaki A, Misawa H, Yokouchi M, Ohtsubo M, Yoshimura A: Cloning and characterization of novel CIS family genes. Biochem Biophys Res Commun 239:439-446, 1997.
65. Suzuki R, Sakamoto H, Yasukawa H, Masuhara M, Wakioka T, Sasaki A, Yuge K, Komiya S, Inoue A, Yoshimura A: CIS3 and JAB have different regulatory roles in interleukin-6 mediated differentiation and STAT3 activation in M1 leukemia cells. Oncogene 17:2271-2278, 1998.
66. Matsumoto A, Seki Y, Kubo M, Ohtsuka S, Suzuki A, Hayashi I, Tsuji K, Nakahata T, Okabe M, Yamada S, Yoshimura A: Suppression of STAT5 functions in liver, mammary glands, and T cells in cytokine-inducible SH2-containing protein 1 transgenic mice. Mol Cell Biol 19:6396-6407, 1999.
67. Verdier F, Chretien S, Muller O, Varlet P, Yoshimura A, Gisselbrecht S, Lacombe C, Mayeux P: Proteasomes regulate erythropoietin receptor and signal transducer and activator of transcription 5 (STAT5) activation: possible involvement of the ubiquinated Cis protein. J Biol Chem 273:28185-28190, 1998.
68. Hansen JA, Lindberg K, Hilton DJ, Nielsen JH, Billestrup N: Mechanism of inhibition of growth hormone feceptor signaling by suppressor of cytokine signaling proteins. Mol Endocrinol 13:1832-1843, 1999.
69. Nicholson SE, Willson TA, Farley A, Starr R, Zhang JG, Baca M, Alexander WS, Metcalf D, Hilton DJ, Nicola NA: Mutational analyses of the SOCS proteins suggest a dual domain requirement but distinct mechanisms for inhibition of LIF and IL-6 signal transduction. EMBO J 18:375-385, 1999.
70. Nicholson SE, DeSouza D, Fabri LJ, Corbin J, Willson TA, Zhang JG, Silva A, Asimakis M, Farley A, Nash AD, Metcalf D, Hilton DJ, Nicola NA, Baca M: Suppressor of cytokine signaling-3 preferentially binds to the SHP-2 binding site on the shared cytokine receptor subunit gp130. Proc Natl Acad Sci USA 97:6493-6498, 2000.
71. Starr R, Metcalf D, Elefanty AG, Brysha M, Willson TA, Nicola NA, Hilton DJ, Alexander WS: Liver degeneration and lymphoid deficiencies in mice lacking suppressor of cytokine signaling-1. Proc Natl Acad Sci USA 95:14395-14399, 1998.
72. Toyonga T, Hino O, Sugai S, Wakasugi S, Abe K, Shichiri M, Yamamura K: Chronic active hepatitis in transgenic mice expressing interferon-gamma in the liver Proc Natl Acad Sci USA 91:614-618, 1994.
73. Gresser L, Aguet M, Morel-Maroger L, Woodrow D, Puvion-Dutilleul F, Gullion J-C, Maury C: Electrophoretically pure mouse interferon inhibits growth, induces liver and kidney lesions, and kills suckling mice. Am J Pathol 102:396-402, 1981.
74. Alexander WS, Starr R, Fenner JE, Scott CL, Handman E, Sprigg NS, Corbin JE, et al.: SOCS-1 is a critical inhibitor of interferon gamma signaling and prevents the potentially fatal neonatal action of this cytokine. Cell 98:597-608, 1999.
75. Marine JC, Topham DJ, McKay C, Wang D, Parganas E, Stravopodis D, Yoshimura A, Ihle JN: SOCS1 deficiency causes a lymphocyte-dependent perinatal lethality. Cell 98:609-616, 1999.
76. Naka T, Matsumoto T, Narazaki M, Fujimoto M, Morita Y, Ohsawa Y, Saito H, Nagasawa T, Uchiyama Y, Kishimoto T: Accelerated apoptosis of lymphocytes by augmented induction of Bax in SSI-1 (Stat-induced STAT inhibitor-1) deficient mice. Proc Natl Acad Sci USA 95:15577-15582, 1998.
77. Sakamoto H, Yasulawa H, Masuhara M, Tanimura S, Sasaki A, Yuge K, Ohtsubo M, et al.: A Janus kinase inhibitor, JAB, is an interferon-inducible gene and confers resistance to interferons. Blood 92:1668-1676, 1998.
78. Metcalf D, Greenhalgh CJ, Viney E, Willson TA, Starr R, Nicola NA, Hilton DJ, Alexander WS: Gigantism in mice lacking suppressor of cytokine signalling-2. Nature 405:1069-1073, 2000.
79. Ram PA, Waxman DJ: SOCS/CIS protein inhibition of growth hormone simulated STAT5 signaling by multiple mechanisms. J Biol Chem 274:35553-35561, 1999.
80. Favre H, Benhamou A, Finidori J, Kelly PA, Edery M: Dual effects of suppressor of cytokine signaling (SOCS-2) on growth hormone signal transduction. FEBS Lett 453:63-66, 1999.
81. Dey BR, Spence SL, Nissley P, Furlanetto RW: Interaction of human suppressor of cytokine signaling (SOCS)-2 with the insulin-like growth factor-I receptor. J Biol Chem 273:24095-24101, 1998.
82. Marine JC, McKay C, Wang D, Topham DJ, Parganas E, Nakajima H, Sasaki A, Yoshimura A, Ihle JN: SOCS3 is essential in the regulation of fetal erythropoieses Cell 98:617-627, 1999.
83. Sasaki A, Yasukawa H, Shouda T, Kitamura T, Dikic I, Yoshimura A: CIS3/ SOCS-3 suppresses erythropoietin (EPO) signaling by binding the EPO receptor and JAK2. J Biol Chem 275:29338-29347, 2000.
84. Conception P, Seiliez I, Thissen JP, Le Cam A: Regulation of expression of the rat SOCS-3 gene in hepatocytes by growth hormone, interleukin-6, and glucocorticoids. Eur J Biochem 267:5849-5857, 2000.
85. Bjorbaek C, Elmquist JK, Frantz JD, Shoelson SE, Fleir JS: Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol Cell 1:619-625, 1998.
86. Bjorbaek C, El-Haschimi K, Frantz JD, Flier JS: The role of leptin signaling and leptin resistance. J Biol Chem 274:30059-30065, 1999.
87. Wang Z, Zhou YT, Kakuma T, Lee Y, Kalra SP, Kalra PS, Pan W, Unger RH: Leptin resistance of adipocytes in obesity: role of suppressors of cytokine signaling. Biochem Biophys Res Commun 277:20-26, 2000.
88. Emilsson V, Arch JRS, de Groot RP, Lister CA, Cawthorne MA: Leptin treatment increases suppressors of cytokine signaling in central and peripheral tissues. FEBS Lett 455:170-174, 1999.
89. Wang Z, Zhou YT, Kakuma T, Lee Y, Kalra SP, Kalra PS, Pan W, Unger RH: Leptin resistance of adipocytes in obesity: the role of suppressors of cytokine signaling. Biochem Biophys Res Commun 277:20-26, 2000.
90. Emanuelli B, Peraldi P, Filloux C, Sawka-Verhelle D, Hilton D, Van Obberghen E: SOCS-3 is an insulin-induced negative regulator of insulin signaling. J Biol Chem 275:15985-15991, 2000.
91. Dey BR, Furlanetto RW, Nissley P: Suppressor of cytokine signaling (SOCS)-3 protein interacts with the insulin-like growth factor-I receptor. Biochem Biophys Res Commun 278:38-43, 2000.
92. Mao Y, Ling PR, Fitzgibbons TP, McCowen KC, Frick GP, Bistrian BR, Smith RJ: Endotoxin-induced inhibition of growth hormone signaling in rat liver in vivo. Endocrinology 140:5505-5515, 1999.
93. Ogle CK, Kong F, Guo X, Wells, DA, Aosasa S, Noel G, Horseman N: The effect of burn injury on suppressors of cytokine signaling. SHOCK 14:392-399, 2000.