Protein kinase Cθ, a selective upstream regulator of JNK/SAPK and IL-2 promoter activation in Jurkat T cells

Abstract

The predominant expression of protein kinase C (PKC) theta in T cells (J. Biol. Chem. 1993. 268: 4997-5004), its isoenzyme-specific ability to stimulate AP-1 transcriptional activity (Mol. Cell. Biol. 1996. 16: 1842-1850) and the recent discovery of its selective and antigen-dependent colocalization with the contact region between T cells and antigen-presenting cells (Nature 1997. 385: 83-89) suggest that, among the PKC family members, PKCtheta plays a specialized role in T cell activation. By investigating the downstream effectors of PKCtheta we now demonstrate a direct and isoenzyme-specific contribution of PKCtheta to c-Jun-N-terminal kinase/stress-activated protein kinase (JNK/SAPK) but not extracellular regulated kinase (ERK) activation. Expression of a constitutively active (CA) form of PKCtheta (but not CA-PKCalpha, epsilon and lambda/iota) resulted in strong activation of JNK/SAPK and expression of a dominant-negative form of PKCtheta interfered with the endogenous activation signal for JNK/SAPK. Importantly, Ca2+ ionophore and CA-PKCtheta (but not CA-PKCalpha, epsilon and lambda/iota) caused synergistic activation of the IL-2 promoter. Together, these data establish that PKCtheta is required for activation of JNK/SAPK signaling leading to IL-2 promoter transcription in T lymphocytes.

A Novel Long Chain Polyunsaturated Fatty Acid, β-Oxa 21:3n-3, Inhibits T Lymphocyte Proliferation, Cytokine Production, Delayed-Type Hypersensitivity, and Carrageenan-Induced Paw Reaction and Selectively Targets Intracellular Signals

“…Indeed, PKC-␣, PKC-⑀ (27), and PKC- (28) have been demonstrated to regulate the activities of ERK and JNK, respectively, in T cells, and studies in smooth muscle cells have demonstrated that PKC-␦ is involved in regulating p38 activity (37). The ability of ␤-oxa 21:3n-3 to partially inhibit ERK, but not JNK activity is consistent with suppression of PKC-⑀, but not PKC-translocation.…”

“…Several PKC isozymes have been demonstrated to regulate the activity of the MAP kinases and the production of lymphokines. PKC-␣ and PKC-⑀ have been shown to regulate ERK (27), whereas PKC-regulates JNK (28,29). To further characterize the reduction in PKC translocation, the ability of ␤-oxa 21:3n-3 and 22:6n-3 to inhibit individual isozyme translocation was examined.…”

“…Each of the MAP kinases, ERK, JNK, and p38, have been demonstrated to play central roles in T cell proliferation and cytokine production (18,27,28,30). Thus, the effects of the ␤-oxa fatty acid on the activity of ERK, JNK, and p38 were examined.…”

Regulation of Protein Kinase Cθ Function during T Cell Activation by Lck-mediated Tyrosine Phosphorylation

“…Previous reports have shown that among several PKC isoforms tested, only PKC was capable of significantly stimulating Ras-dependent transcription from an AP-1 element in EL4 leukemic T cells (10). PKC also specifically cooperates with calcineurin and plays a critical role in c-Jun NH 2 -terminal kinase activation and induction of the interleukin-2 gene (11,12). Recent reports indicated that among different T cell-expressed PKC isoforms, PKC was the only one to colocalize precisely with the TCR⅐CD3 complex in the contact region between antigen-specific T cells and antigen-presenting cells.…”

Differential Regulation of Th2 and Th1 Lung Inflammatory Responses by Protein Kinase Cθ

“…Furthermore, studies using pharmocological inhibitors and PKC antisense RNA and overexpression studies using dominant negative and constitutively active mutant proteins have established a role for PKC in activation of AP-1 (7) and NF-B (8,9). PKC also synergizes with calcineurin to activate NFAT and IL-2 transcription (10,11), and with Vav to mediate IL-4 gene expression in response to CD28 costimulation (12).…”