T Cell Proliferation in Response to Interleukins 2 and 7 Requires p38MAP Kinase Activation

Interleukin-2 (IL-2) is a potent T cell mitogen. However, the signaling pathways by which IL-2 mediates its mitogenic effect are not fully understood. One of the members of the mitogen-activated protein kinase (MAPK) family, p42/44MAPK (ERK2/1), is known to be activated by IL-2. We have now investigated the response to IL-2 of two other members of the MAP kinase family, p54MAP kinase (stress-activated protein kinase (SAPK)/Jun-N-terminal kinase (JNK)) and p38MAP kinase (p38/Mpk2/CSBP/RK), which respond primarily to stressful and inflammatory stimuli (e.g. tumor necrosis factor-α, IL-1, and lipopolysaccharide). Here we show that IL-2, and another T cell growth factor, IL-7, activate both SAPK/JNK and p38MAP kinase. Furthermore, inhibition of p38MAP kinase activity with a specific pyrinidyl imidazole inhibitor SB203580 that prevents activation of its downstream effector, MAPK-activating protein kinase-2, correlated with suppression of IL-2- and IL-7-driven T cell proliferation. These data indicate that in T cells p38MAP kinase has a role in transducing the mitogenic signal. Interleukin-2 (IL-2) is a potent T cell mitogen. However, the signaling pathways by which IL-2 mediates its mitogenic effect are not fully understood. One of the members of the mitogen-activated protein kinase (MAPK) family, p42/44MAPK (ERK2/1), is known to be activated by IL-2. We have now investigated the response to IL-2 of two other members of the MAP kinase family, p54MAP kinase (stress-activated protein kinase (SAPK)/Jun-N-terminal kinase (JNK)) and p38MAP kinase (p38/Mpk2/CSBP/RK), which respond primarily to stressful and inflammatory stimuli (e.g. tumor necrosis factor-α, IL-1, and lipopolysaccharide). Here we show that IL-2, and another T cell growth factor, IL-7, activate both SAPK/JNK and p38MAP kinase. Furthermore, inhibition of p38MAP kinase activity with a specific pyrinidyl imidazole inhibitor SB203580 that prevents activation of its downstream effector, MAPK-activating protein kinase-2, correlated with suppression of IL-2- and IL-7-driven T cell proliferation. These data indicate that in T cells p38MAP kinase has a role in transducing the mitogenic signal. Interleukin-2 (IL-2) 1The abbreviations used are:ILinterleukinERKextracellular signal-regulated kinaseMAPmitogen-activated proteinMAPKMAP kinaseMAPKAPMAPK-activating proteinSAPKstress-activated protein kinaseJNKJun-N-terminal kinaseTNFtumor necrosis factorTNFRTNF receptorGSTglutathioneS-transferase. is a key factor in driving the proliferation of activated T lymphocytes; a crucial event in mounting an effective immune response (1Smith K.A. Science. 1988; 240: 1169-1176Google Scholar). The high affinity IL-2 receptor is a heterotrimeric complex composed of α, β, and γc subunits, the latter being shared with the receptors for IL-4, IL-7, IL-9, and IL-15, other T cell growth factor cytokines (2Theze J. Alzari P.M. Bertoglio J. Immunol. Today. 1996; 17: 481-486Google Scholar). interleukin extracellular signal-regulated kinase mitogen-activated protein MAP kinase MAPK-activating protein stress-activated protein kinase Jun-N-terminal kinase tumor necrosis factor TNF receptor glutathioneS-transferase. Ligation of IL-2 to its receptor initiates the activation of several intracellular enzymes including the tyrosine kinases: Jak1, Jak3 (3Russell S.M. Johnston J.A. Noguchi M. Kawamura M. Bacon C.M. Friemann M. Berg M. McVicar D.W. Witthuhn B.A. Silvennoinen O. Goldman A.S. Schmalsteig F.C. Ihle J.N. O'Shea J.J. Leonard W.J. Science. 1994; 266: 1042-1045Google Scholar,4Miyazaki T. Kawahara A. Fujii H. Nakagawa Y. Minami Y. Liu Z.-Y. Oishi I. Silvennoinen O. Witthuhn B.A. Ihle J. Taniguchi T. Science. 1994; 266: 1045-1047Google Scholar), Syk (5Minami Y. Nakagawa Y. Kawahara A. Miyazaki T. Sada K. Yamamura H. Taniguchi T. Immunity. 1995; 2: 89-100Google Scholar) and p56lck (6Minami Y. Kono T. Yamada K. Kobayashi N. Kawahara A. Perlmutter R.M. Taniguchi T. EMBO J. 1993; 12: 759-768Google Scholar); phosphatidylinositol 3′-kinase (7Augustine J.A. Sutor S.L. Abraham R.T. Mol. Cell. Biol. 1991; 11(9): 4431-4440Google Scholar,8Merida I. Diez E. Gaulton G.N. J. Immunol. 1991; 147: 2202-2207Google Scholar), and p70 S6 kinase (9Calvo V. Crews C.M. Vik T.A. Bierer B. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 7571-7575Scopus (167) Google Scholar, 10Kuo C.J. Jongkyeong C. Fiorentino D.F. Flanagan W.M. Blenis J. Crabtree G.R. Nature. 1992; 358: 70-73Google Scholar, 11Sawami H. Terada N. Franklin R.A. Okawa H. Uchiyama T. Lucas J.L. Gelfand E.W. J. Cell. Physiol. 1992; 151: 367-377Google Scholar). Furthermore, IL-2 activates ERK (12Perkins G.R. Marvel J. Collins M.K.L. J. Exp. Med. 1993; 178: 1429-1434Google Scholar, 13Fairhurst R.M. Daeipour M. Amaral M.C. Nel A.E. Immunology. 1993; 79: 112-118Google Scholar, 14Crawley J.B. Willcocks J. Foxwell B.M.J. Eur. J. Immunol. 1996; 26: 2717-2733Google Scholar) via a cascade of events involving the assembly of the Shc·Grb-2·mSOS complex (15Ravichandran K.S. Burakoff S. J. Biol. Chem. 1994; 269: 1599-1602Google Scholar), the regulation of the GTPase p21ras (16Satoh T. Nakafuku M. Miyajima A. Kaziro Y. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 3314-3318Google Scholar, 17Graves J.D. Downward J. Izquierdo M. Rayter S. Warne P.H. Cantrell D.A. J. Immunol. 1992; 148: 2417-2422Google Scholar), the activation of Raf-1 (18Turner B.C. Rapp U.R. App H. Greene M. Dobashi K. Reed J. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 1227-1231Google Scholar, 19Zmuidzinas A. Mamon H.J. Roberts T.M. Smith K.A. Mol. Cell. Biol. 1991; 11: 2794-2803Google Scholar), and by inference MEK1/2. However, the contribution of all these events to the proliferative activity of IL-2 is unclear. While the activation of Jak3 (4Miyazaki T. Kawahara A. Fujii H. Nakagawa Y. Minami Y. Liu Z.-Y. Oishi I. Silvennoinen O. Witthuhn B.A. Ihle J. Taniguchi T. Science. 1994; 266: 1045-1047Google Scholar, 20Nosaka T. van Deursen J.M.A. Tripp R.A. Thierfelder W.E. Witthuhn B.A. McMickle A.P. Doherty P.C. Grosveld G.C. Ihle J.N. Science. 1995; 270: 800-802Google Scholar, 21Thomis D.C. Gurniak C.B. Tivol E. Sharpe A.H. Berg L.J. Science. 1995; 270: 794-797Google Scholar) and p70 S6 kinase (10Kuo C.J. Jongkyeong C. Fiorentino D.F. Flanagan W.M. Blenis J. Crabtree G.R. Nature. 1992; 358: 70-73Google Scholar, 22Dumont F.J. Staruch M.J. Koprak S.L. Melino M.R. Sigal N.H. J. Immunol. 1990; 144: 251-258Google Scholar) are essential for the transduction of the mitogenic signal, a variety of studies have suggested that the activation of p56lck (6Minami Y. Kono T. Yamada K. Kobayashi N. Kawahara A. Perlmutter R.M. Taniguchi T. EMBO J. 1993; 12: 759-768Google Scholar, 23Hatakeyama M. Kono T. Kobayashi N. Kawahara A. Levin S.D. Perlmutter R.M. Taniguchi T. Science. 1991; 252: 1523-1528Google Scholar), Syk (24Turner M. Mee P.J. Costello P.S. Williams O. Price A.A. Duddy L.P. Furlong M.T. Geahlen R.L. Tybulewicz V.L.J. Nature. 1995; 378: 298-302Google Scholar), Jak1 (25Higuchi M. Asao H. Tanaka N. Oda K. Takeshita T. Nakamura M. Van-Snick J. Sugamura K. Eur. J. Immunol. 1996; 26: 1322-1327Google Scholar), and the p21ras/ERK1/2 pathway are not required for the proliferative response (14Crawley J.B. Willcocks J. Foxwell B.M.J. Eur. J. Immunol. 1996; 26: 2717-2733Google Scholar, 26Evans G.A. Goldsmith M.A. Johnston J.A. Xu W. Weiler S.R. Erwin R. Howard O.M.Z. Abraham R.T. O'Shea J.J. Greene W.C. Farrar W.L. J. Biol. Chem. 1995; 48: 28858-28863Google Scholar, 27Satoh T. Minami Y. Kono T. Yamada K. Kawahara A. Taniguchi T. Kaziro Y. J. Biol. Chem. 1992; 267: 25423-25427Google Scholar). Furthermore, while the activation of Jak1 and Jak3 are common to the other T cell growth factors, IL-4 (28Witthuhn B.A. Silennioinen O. Miura O. Lai K.S. Cwik C. Liu E. Ihle J. Nature. 1994; 370: 153-157Google Scholar), IL-7 (29Foxwell B.M.J. Beadling C. Guschin D. Kerr I. Cantrell D. Eur J. Immunol. 1995; 25: 3041-3046Google Scholar, 30Dadi H. Ke S. Roifman C.M. Blood. 1994; 84: 1579-1586Google Scholar), and IL-9 (31Yin T. Yang L. Yang Y.C. Blood. 1995; 85: 3101-3106Google Scholar), activation of the other IL-2-mediated events, with the exception of the IL-7-induced activation of p56lck (32Page T.H. Lali F.V. Foxwell B.M.J. Eur. J. Immunol. 1995; 25: 2956-2960Google Scholar), has not been observed. The apparent redundancy of ERK activation in T cell proliferation is in contrast to other cellular systems, where these kinases have been implicated in mitogenic responses to growth factors (33Seger R. Krebs E.G. FASEB J. 1995; 9: 726-735Scopus (3210) Google Scholar). This functional link is supported by the transforming potential of the proximal activators of this pathway, i.e. oncogenic Ras (reviewed in Ref. 34Barbacid M. Annu. Rev. Biochem. 1987; 50: 779-827Google Scholar) and Raf (35Rapp U.R. Goldsborough M.D. Mark G.E. Bonner T.I. Groffen J. Reynolds F.H.J. Stephenson J.R. Proc. Natl. Acad. Sci. U. S. A. 1983; 80: 4218-4222Google Scholar) and a constitutively active form of MEK1 (36Cowley S. Paterson H. Kemp P. Marshall C.J. Cell. 1994; 77: 841-852Google Scholar), as well as by studies with dominant-negative and antisense cDNA (37Pages G. Lenormand P. L'Allemain G. Chambard J.-C. Meloche S. Pouyssegur J. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 8319-8323Google Scholar). The inhibition of fibroblast proliferation by a specific inhibitor of MEK1, PD098059 (38Dudley D.T. Pang L. Decker S.J. Bridges A.J. Saltiel A.R. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 7686-7689Google Scholar), further supports a role for this pathway in proliferation. Recently two other subgroups of the MAP kinase family have been characterized, SAPK/JNK and p38MAP kinase. These kinases respond to a variety of physicochemical stresses (e.g. UV light, translational inhibitors, hyperosmolarity), lipopolysaccharide, and the pro-inflammatory cytokines TNF-α and IL-1 (39Kyriakis J.M. Banerjee P. Nikolakaki E. Dai T. Rubie E.A. Ahmad M.F. Avruch J. Woodgett J.R. Nature. 1994; 369: 156-160Google Scholar, 40Han J. Lee J.D. Bibbs L. Ulevitch R.J. Science. 1994; 265: 808-811Google Scholar, 41Freshney N.W. Rawlinson L. Guesdon F. Jones E. Cowley S. Hsuan J. Saklatvala J. Cell. 1994; 78: 1039-1049Google Scholar, 42Lee J.C. Laydon J.T. McDonnell P.C. Gallagher T.F. Kumar S. Green D. McNulty D. Blumenthal M.-J. Heys M.J. Landvatter S.W. Strickler J.E. McLaughlin M.M. Siemens I.R. Fisher S.M. Livi G.P. White J.R. Adams J.L. Young P.R. Nature. 1994; 372: 739-746Google Scholar, 43Hibi M. Lin A. Smeal T. Minden A. Karin M. Genes Dev. 1993; 7: 2135-2148Google Scholar). Unlike ERK, these “stress kinases” have not been implicated previously in mitogenesis. The response of these enzymes to IL-2, other T cell growth factors, or other cytokines barring those mentioned above has not been investigated previously, although SAPK/JNK has been shown to be activated in T cells by co-stimulation through CD3 and CD28 (44Su B. Jacinto E. Hibi M. Kallunki T. Karin M. Ben-Neriah Y. Cell. 1994; 77: 727-736Google Scholar). This study shows that both SAPK/JNK and p38MAP kinase are activated by IL-2. In addition (which is not the case for ERK) they are also activated by IL-7. The inhibition of p38MAP kinase activity by the specific inhibitor SB203580 resulted in suppression of T cell proliferation in response to IL-2 and IL-7, suggesting that rather than being solely involved in stress responses, in T cells at least, p38MAP kinase is required to transduce the mitogenic signal. IL-7 and IL-2 were kindly provided by Dr. C. Faltynek (Sterling Winthrope, Malvern, PA) and Dr. P. Lomedico, (Roche Inc., Nutley, NJ), respectively. Rabbit antisera to SAPK/JNK were raised to the N-terminal peptide sequence, GVVKGQPSPSAQVQQ, and to p38MAP kinase as reported previously (45Saklatvala J. Rawlinson L. Waller R.J. Sarsfield S. Lee J.C. Morton L.F. Barnes M.J. Farndale R.W. J. Biol. Chem. 1996; 271: 6586-6589Google Scholar). Antibody to MAPKAP kinase-2 was from Upstate Biotechnology, Inc. (Lake Placid, NY), ERK was from Santa Cruz (Santa Cruz, CA) and c-Myc was generously provided by Dr. G. Evan (Imperial Cancer Research Fund, London). The p38MAPK inhibitor SB203580 was generously provided by Dr. J. Lee, SmithKline Beecham Pharmaceuticals (King of Prussia, PA). GST-Jun (2–89) and GST-ATF2 (19–96) were purified by standard techniques. The murine cytokine-dependent T cell line, CT6 (kindly provided by Genentech, South San Francisco, CA) was maintained and proliferation assays and Western immunoblotting c-Myc and ERK performed as described previously (14Crawley J.B. Willcocks J. Foxwell B.M.J. Eur. J. Immunol. 1996; 26: 2717-2733Google Scholar, 46Willcocks J.L. Hales A. Page T.H. Foxwell B.M.J. Eur. J. Immunol. 1993; 23: 716-720Google Scholar). Cell viability was assessed by the amount of merocyanine 540 (Sigma) incorporated into the cell membrane of live gated cells (47Mower D.A. Peckham D.W. Illera V.A. Fishbaugh J.K. J. Immunol. 1994; Scholar). T cell and proliferation were as described previously T.H. Willcocks J.L. D.A. Foxwell B.M.J. J. Immunol. 1993; 151: Scholar). SB203580 was to the cells to the addition of where were at in were for to were for at with with specific Inc., were with to Western immunoblotting and a further two with kinase to kinase assays In kinase assays for SAPK/JNK were performed in of and of or were by addition of of for at were by with the in kinase assays for p38MAP kinase (which is not to MAPKAP and were purified from and was as described previously N.W. Rawlinson L. Guesdon F. Jones E. Cowley S. Hsuan J. Saklatvala J. Cell. 1994; 78: 1039-1049Google Scholar). the were of kinase of kinase which been previously by with protein and the was and as for the SAPK/JNK were by and were at the in MAPKAP kinase-2 the activated was from of cell for at The as for the p38MAP kinase and SAPK/JNK in of kinase of peptide D. B. P. Biochem. J. 1993; were with of of at were by the of and into in and in the were to SAPK/JNK activation was by of M. Lin A. Smeal T. Minden A. Karin M. Genes Dev. 1993; 7: 2135-2148Google Scholar) or S. D. B. R.J. Science. 1995; 267: Scholar) as from and murine T The was activated from as with that from cells a of the CT6 cells with IL-7 also activated this kinase SAPK/JNK activation was for both cytokines and was at This with the proliferative response of CT6 to J.L. Hales A. Page T.H. Foxwell B.M.J. Eur. J. Immunol. 1993; 23: 716-720Google Scholar). activated SAPK/JNK was also from T cells with or to TNF-α kinase activity was with a and which the of the stressful and inflammatory stimuli that activate SAPK/JNK also activate a p38MAP kinase. We investigated this stress kinase respond to T cell The activity of p38MAP kinase from CT6 cells was by a kinase cascade involving kinase (which is not MAPKAP kinase-2 J. P. S. M. A. D. T. A.R. Cell. 1994; 78: and its N.W. Rawlinson L. Guesdon F. Jones E. Cowley S. Hsuan J. Saklatvala J. Cell. 1994; 78: 1039-1049Google Scholar). in was with p38MAP kinase from cells studies activation by IL-7 was with IL-2 although this has not been apparent in all TNF-α also activated p38MAP kinase as although be that CT6 cells the TNF receptor G.E. R.A. J. Immunol. Scholar), while studies the TNF-α response have used cells that also the kinase activity was by Unlike p38MAP kinase has not been previously shown to be activated in T of CT6 cells with the specific p38MAP kinase proliferation by IL-2 or IL-7 is for inhibition of TNF-α by M. Williams and B. M. J. and for (45Saklatvala J. Rawlinson L. Waller R.J. Sarsfield S. Lee J.C. Morton L.F. Barnes M.J. Farndale R.W. J. Biol. Chem. 1996; 271: 6586-6589Google Scholar). We the effect of this inhibitor T cells from and These were with and to to IL-2 and IL-7. SB203580 the proliferation a to that in the T cell The was not at the used as by merocyanine in with cell (47Mower D.A. Peckham D.W. Illera V.A. Fishbaugh J.K. J. Immunol. 1994; Scholar) all responses to the of c-Myc by IL-2 or IL-7 (14Crawley J.B. Willcocks J. Foxwell B.M.J. Eur. J. Immunol. 1996; 26: 2717-2733Google Scholar) was by SB203580 The effect of SB203580 T cell proliferation to this correlated with inhibition of known of p38MAP kinase. MAPKAP kinase-2 is and activated by p38MAP kinase in a of cell N.W. Rawlinson L. Guesdon F. Jones E. Cowley S. Hsuan J. Saklatvala J. Cell. 1994; 78: 1039-1049Google Scholar, J. P. S. M. A. D. T. A.R. Cell. 1994; 78: Scholar), and this is by SB203580 A. J. R. P. Gallagher T.F. Young P.R. Lee J.C. 1995; Scholar). MAPKAP kinase-2 was activated by IL-2 in a as by assays of the from CT6 was at the proliferative response of the cells a The activation of the was by SB203580 in the in with the in inhibition of p38MAP kinase A. J. R. P. Gallagher T.F. Young P.R. Lee J.C. 1995; Scholar) and studies MAPKAP kinase-2 Y. J. A. S. P. M.J. EMBO J. 1996; Scholar). was MAPKAP kinase-2 activity in with antisera In studies of ERK by that the was by SB203580 as was the SAPK/JNK activation by in specific the of the This study shows that the previously p38MAP kinase and SAPK/JNK are activated in T cells by the mitogenic cytokines IL-2 and IL-7. is that p38MAP kinase is involved in transducing these mitogenic This is in contrast to ERK, which has been shown previously not to be for T cell proliferation (14Crawley J.B. Willcocks J. Foxwell B.M.J. Eur. J. Immunol. 1996; 26: 2717-2733Google Scholar), the in other cells that is ERK that is required for proliferative and that p38MAP kinase is involved in stress The activation of p38MAP kinase by IL-2 and IL-7 is the of the activation of this kinase in T The of specific pyrinidyl imidazole of p38MAP kinase to its role in T cells to IL-2 or IL-7. These the of TNF-α and IL-1 by with J.C. Laydon J.T. McDonnell P.C. Gallagher T.F. Kumar S. Green D. McNulty D. Blumenthal M.-J. Heys M.J. Landvatter S.W. Strickler J.E. McLaughlin M.M. Siemens I.R. Fisher S.M. Livi G.P. White J.R. Adams J.L. Young P.R. Nature. 1994; 372: 739-746Google Scholar), and has been shown to be specific for p38MAP kinase A. J. R. P. Gallagher T.F. Young P.R. Lee J.C. 1995; Scholar). The of that proliferation were than those required to the activation of the MAPKAP This in be for by the of the two is a complex response and is the other a The that SB203580 another protein kinase to IL-2 is as has activity a of other kinases at high A. J. R. P. Gallagher T.F. Young P.R. Lee J.C. 1995; Scholar). However, the of be These that p38MAP kinase has a role in the proliferative response of T cells to The of the signaling pathways to the activation of p38MAP kinase by IL-2 and IL-7 is an The activation of R. J. A. A.R. P. Eur. J. Immunol. 1996; Scholar, A. G. N. Jones M. R. P. A.R. EMBO J. 1996; Scholar), the and and kinase have been shown or implicated in the activation of p38MAP kinase in a variety of cells J.A. Xu S. M.R. S. Mol. Cell. Biol. 1996; Scholar, A. Lin A. A. Karin M. Cell. 1995; Scholar), the response of these to IL-2 is which is activated by IL-2 (16Satoh T. Nakafuku M. Miyajima A. Kaziro Y. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 3314-3318Google Scholar, 17Graves J.D. Downward J. Izquierdo M. Rayter S. Warne P.H. Cantrell D.A. J. Immunol. 1992; 148: 2417-2422Google Scholar), has also been suggested as a proximal for the kinase A. Lin A. M. C. B. R.J. Karin M. Science. 1994; 266: Scholar). IL-7 not to the cascade (14Crawley J.B. Willcocks J. Foxwell B.M.J. Eur. J. Immunol. 1996; 26: 2717-2733Google Scholar). IL-2 and IL-7 both activate tyrosine kinases Jak1, and p56lck (3Russell S.M. Johnston J.A. Noguchi M. Kawamura M. Bacon C.M. Friemann M. Berg M. McVicar D.W. Witthuhn B.A. Silvennoinen O. Goldman A.S. Schmalsteig F.C. Ihle J.N. O'Shea J.J. Leonard W.J. Science. 1994; 266: 1042-1045Google Scholar, T. Kawahara A. Fujii H. Nakagawa Y. Minami Y. Liu Z.-Y. Oishi I. Silvennoinen O. Witthuhn B.A. Ihle J. Taniguchi T. Science. 1994; 266: 1045-1047Google Scholar, Y. Kono T. Yamada K. Kobayashi N. Kawahara A. Perlmutter R.M. Taniguchi T. EMBO J. 1993; 12: 759-768Google Scholar, B.M.J. Beadling C. Guschin D. Kerr I. Cantrell D. Eur J. Immunol. 1995; 25: 3041-3046Google Scholar, T.H. Lali F.V. Foxwell B.M.J. Eur. J. Immunol. 1995; 25: 2956-2960Google Scholar), is that these be involved in the signaling cascade to these and this is being the events to the kinase are and data have shown that the of c-Myc was not and that the pathway required for this event is In other cells p38MAP kinase has been implicated in the translational of TNF by J.C. Laydon J.T. McDonnell P.C. Gallagher T.F. Kumar S. Green D. McNulty D. Blumenthal M.-J. Heys M.J. Landvatter S.W. Strickler J.E. McLaughlin M.M. Siemens I.R. Fisher S.M. Livi G.P. White J.R. Adams J.L. Young P.R. Nature. 1994; 372: 739-746Google Scholar). p38MAP kinase has also been shown to and activate the factors and Y. J. A. S. P. M.J. EMBO J. 1996; Scholar), M.A. R. EMBO J. 1996; Scholar), D. Science. 1996; Scholar), and J. A.J. T. B. R.J. Mol. Cell. Biol. 1996; Scholar). of these are known to be activated by IL-2, and although is involved in by the is not required for cell proliferation T. Minami Y. Kono T. Yamada K. Kawahara A. Taniguchi T. Kaziro Y. J. Biol. Chem. 1992; 267: 25423-25427Google Scholar). The role by SAPK/JNK in IL-2 and IL-7 not be as specific inhibitor for this kinase. However, IL-2 the of in which SAPK/JNK has been implicated M. Lin A. Smeal T. Minden A. Karin M. Genes Dev. 1993; 7: 2135-2148Google Scholar). The activation of SAPK/JNK has been previously in T cells (44Su B. Jacinto E. Hibi M. Kallunki T. Karin M. Ben-Neriah Y. Cell. 1994; 77: 727-736Google Scholar) in response to of CD3 and This a signal, a to T However, IL-2 IL-7 intracellular (2Theze J. Alzari P.M. Bertoglio J. Immunol. Today. 1996; 17: 481-486Google Scholar), and the of activation of SAPK/JNK in T cells by cytokines is from that described is known of the response of B. J. T. J. Ulevitch R.J. R.J. Science. 1995; 267: Scholar, I. R.T. K. Woodgett J.R. Avruch J. J.M. Nature. 1994; 372: Scholar) or A. Lin A. M. C. B. R.J. Karin M. Science. 1994; 266: Scholar), which are proximal activators of to IL-2 and IL-7. its activation by growth factors, growth factor cells A. Lin A. A. Karin M. Cell. 1995; Scholar), cells A. T. Williams J.A. J. Biol. Chem. 1996; 271: Scholar), and both and cells P.S. J.N. R.J. J.A. J. Biol. Chem. 1996; 271: Scholar), role for SAPK/JNK in T cell has been In we have shown that the previously stress-activated kinases p38MAP kinase and SAPK/JNK are activated in T cells by the mitogenic cytokines IL-2 and IL-7. Furthermore, the specific inhibitor SB203580 a previously role for p38MAP kinase in has been observed. p38MAP kinase is of the of IL-2 and IL-7 signaling pathways that be a role in T cell proliferation. The of these kinases in inflammatory responses has as The that these kinases are also activated by T cell mitogenic cytokines and that at p38MAP kinase has a role in transducing the proliferative response have for of these