[Frontiers in Bioscience 2, d49-60, February 15, 1997]

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Javier Gómez, David García-Domingo, Carlos Martínez-A.1 and Angelita Rebollo

Department of Immunology and Oncology, Centro Nacional de Biotecnología, Campus de Cantoblanco, E-28049 Madrid, Spain

Received 1/21/97; Accepted 1/30/97; On-line 2/15/97

7. Role of NF-kappaB in IL-2-triggered T cell responses

NF-kappaB activation following ligation of the IL-2 receptor is an event involved in the signal transduction pathways triggered by this lymphokine. It remains to be defined, however, which cellular responses are controlled by NF-kappaB-dependent gene transactivation and which signals are involved in activation and nuclear translocation of NF-kappaB dimers.

The IL-2 receptor signaling system has been explained as a three-channel model, in which at least three different pathways mediate the flow of mitogenic and survival-promoting signals (107, 108). According to this scheme, one of the pathways (channel 1) proceeds through protein tyrosine kinase activity, Ras and the MAPK cascade, leading to expression of the protooncogenes c-fos and c-jun. Channel 2 is proposed to be initiated by the protein tyrosine kinase Syk and to be responsible for c-myc gene induction. Finally, channel 3 results in bcl-2 expression, and progression through a Rho-, PI3 kinase- and zetaPKC-mediated signaling pathway (96; Gómez et al., submitted). This last pathway is also involved in IL-2-promoted regulation of actin cytoskeleton organization. In the murine TS1alphaß T cell line, cooperation among the three channels triggers cell proliferation, while cooperation between only two, when one of them is channel 1, maintains cell survival with no mitogenic effect (108).

IL-2 induction of nuclear NF-kappaB dimers with DNA binding activity is sensitive to the immunosuppressant, rapamycin, both in the TS1alphaß and TS1ß cell lines (109). The cellular effects of this drug have been attributed to a specific inhibition of the 70 kDa kinase of the S6 ribosomal protein, p70s6k (110-112). However, rapamycin action also appears to affect PI kinase activities (113-114) and formation of active cyclin-cdk complexes (115). In TS1alphaß cells, rapamycin inhibits IL-2-induced PI3 kinase activity and cell proliferation. Rapamycin also modifies the electrophoretic mobility shift pattern of NF-kappaB induction by IL-2 (109), suggesting that the pathway responsible for NF-kappaB activation and nuclear translocation by IL-2 in TS1alphaß cells is channel 3. Recent evidence indicates that IL-2 stimulation of NF-kappaB in the same cell line is inhibited to a similar extent by Clostridium difficile toxin B, a specific Rho protein inhibitor, or by wortmannin, a compound that produces covalent inactivation of PI3 kinase (Gómez et al., unpublished results). The results suggest that NF-kappaB activation by IL-2 might occur through a Rho-PI3 kinase-zetaPKC pathway that triggers the activation of an IkappaB kinase and subsequent release of free active NF-kappaB complexes. These data support earlier studies that proposed the participation of zetaPKC as a putative inducer of NF-kappaB activation (43). Rho family proteins have also shown implication in the activation of NF-kappaB complexes (83).

One possibility that may be inferred from the above data is that NF-kappaB might be involved in bcl-2 gene induction. In fact, NF-kappaB consensus binding sequences exist within the bcl-2 gene promoter, and our recent evidence indicates that a correlation exists between the IL-2-induced appearance of nuclear active NF-kappaB complexes and bcl-2 expression, whereas none of these events occurs when cells are stimulated with IL-4 (Gómez et al., unpublished results). If these hypotheses prove correct, it might be deduced that NF-kappaB would control both mitogenic and survival signals in IL-2 receptor signaling, as occurs with Rho. Inhibition of Rho activity prevents IL-2-induced proliferation but does not affect cell survival, concurring with the three-channel model applied to the TS1alphaß cell line. Conversely, a constitutively active form of Rho protects TS1alphaß cells from lymphokine withdrawal-induced apoptosis. This latter effect is due to the fact that Ras is active in lymphokine-deprived TS1alphaß cells Rho activation thus complements the Ras signal, providing a rescue pathway that abolishes programmed cell death (Gómez et al., submitted). In summary, NF-kappaB may act as a regulatory step for stimulation of both cell survival and proliferation by IL-2 in T cells. Whether the complete Rho-delivered signal proceeds through NF-kappaB activation or branches at an earlier step will determine whether NF-kappaB control over cellular responses is comparable to that exerted by Rho proteins.