NF-kappa B activation plays an important role in the IL-4-induced protection from apoptosis.

Zamorano J, Mora AL, Boothby M, Keegan AD
Int Immunol. 2001 13 (12): 1479-87

PMID: 11717189 · DOI:10.1093/intimm/13.12.1479

IL-4 alone protects cells from apoptosis by insulin receptor substrate (IRS)-dependent and -independent mechanisms. However, in vivo cells are typically exposed to a number of signals at the same time. To determine the contribution of co-stimulatory signals to the regulation of apoptosis by IL-4, we first analyzed whether tumor necrosis factor (TNF)-alpha, which has been shown to inhibit the activation of IRS-1 by insulin, could modify IL-4 signaling and protection from apoptosis. We found that TNF-alpha cooperates with IL-4 in protecting 32D cells from factor withdrawal-induced apoptosis. This effect was independent of the expression of IRS-1, indicating that this cooperation is via an alternative anti-apoptotic pathway. Moreover, TNF-alpha had no effect on the activation of IRS-1 induced by IL-4. IL-4 enhanced TNF-alpha-induced activation of the transcription factor NF-kappaB. Interestingly, pharmacologic inhibition of NF-kappaB activation or protein synthesis resulted in the induction of cell death that could not be inhibited by IL-4, suggesting that IL-4 cooperates with NF-kappaB to signal protection from apoptosis. Supporting this hypothesis, IL-4 also increased NF-kappaB activation induced by anti-CD3 antibodies in primary T cells and protected them from apoptosis induced by receptor engagement. However, IL-4 was not able to inhibit apoptosis induced by anti-CD3 in T lymphocytes isolated from transgenic mice expressing a dominant-negative form of IkappaBalpha that prevents NF-kappaB activation. Thus, in addition to the previously identified IRS-1 pathway, IL-4-induced protection from apoptosis may also be mediated through cooperation with the NF-kappaB family of transcription factors.

MeSH Terms (18)

Adjuvants, Immunologic Animals Antibodies, Monoclonal Apoptosis CD3 Complex Cell Survival Insulin Receptor Substrate Proteins Interleukin-4 Mice Mice, Transgenic NF-kappa B Phosphoproteins Receptor, Insulin Signal Transduction STAT6 Transcription Factor T-Lymphocytes Trans-Activators Tumor Necrosis Factor-alpha

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