T cell activation signals up-regulate p38 mitogen-activated protein kinaseactivity and induce TNF-alpha production in a manner distinct from LPS activation of monocytes

p38 mitogen-activated protein kinase (MAPK) (p38) is involved in various ce llular responses, including LPS stimulation of monocytes, resulting in prod uction of proinflammatory cytokines such as TNF-alpha. However, the functio n of p38 during antigenic stimulation of T cells is largely unknown, Stimul ation of the human Th cell clone HA-1.70 with either the superantigen staph ylococcal enterotoxin B (SEB) or with a specific antigenic peptide resulted in p38 activation and the release of TNF-alpha. MAPK-activated protein kin ase-2 (MAPKAPK-2), an in vivo substrate for p38, was also activated by T ce ll signaling. SE 203580, a selective inhibitor of p38, blocked p38 and MAPK APK-2 activation in the T cell clone but did not completely inhibit TNF-alp ha release. PD 098059, a selective inhibitor of MAPK kinase 1 (MEK1), block ed activation of extracellular signal-regulated kinase (ERK) and partially blocked TNF-alpha production by the clone. In human peripheral T cells, p38 was not activated by SEE, but rather by CD28 cross-linking, whereas in the human leukemic T cell line Jurkat, p38 was activated by CD3 and CD28 cross -linking in an additive fashion. TNF-alpha! production by peripheral T cell s in response to SEE and anti-CD28 mAb correlated more closely with ERK act ivity than with p38 activity. Therefore, various forms of T cell stimulatio n can activate the p38 pathway depending on the cells examined. Furthermore , unlike LPS-stimulated monocytes, TNF-alpha production by T cells is only partially p38-dependent.