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Tumor necrosis factor alpha-induced activation of c-jun N-terminal kinase is mediated by TRAF2
C Reinhard1, B Shamoon, V Shyamala
1Chiron Corporation, Emeryville, CA 94608, USA.
Abstract:
Tumor necrosis factor alpha (TNF alpha) a pro-inflammatory cytokine is an endogenous mediator of septic shock, inflammation, anti-viral responses and apoptotic cell death. TNF alpha elicits its complex biological responses through the individual or cooperative action of two TNF receptors of mol. wt 55 kDa (TNF-RI) and mol. wt 75 kDa (TNF-RII). To determine signaling events specific for TNF-RII we fused the extracellular domain of the mouse CD4 antigen to the intracellular domain of TNF-RII. Crosslinking of the chimeric receptor using anti-CD4 antibodies initiates exclusively TNF-RII-mediated signals. Our findings show that: (i) TNF-RII is able to activate two members of the MAP kinase family: extracellular regulated kinase (ERK) and c-jun N-terminal kinase (JNK); (ii) TRAF2, a molecule that binds TNF-RII and associates indirectly with TNF-RI, is sufficient to activate JNK upon overexpression; (iii) dominant-negative TRAF2 blocks TNF alpha-mediated JNK activation and (iv) TRAF2 signals the activation of JNK and NF-kappaB through different pathways. Our findings suggest that TNF alpha-mediated JNK activation in fibroblasts is independent of the cell death pathway and that TRAF2 occupies a key role in TNF receptor signaling to JNK.
Insights
Tumor necrosis factor alpha (TNF alpha) signals through TNF-RII to activate MAP kinases like JNK. TRAF2 mediates this TNF-RII signaling, distinct from cell death pathways.
Area of Science:
- Immunology
- Cell Signaling
- Molecular Biology
Background:
- Tumor necrosis factor alpha (TNF alpha) is a key pro-inflammatory cytokine involved in septic shock, inflammation, and apoptosis.
- TNF alpha exerts its effects via two receptors: TNF-RI (55 kDa) and TNF-RII (75 kDa).
- Understanding TNF-RII specific signaling pathways is crucial for elucidating TNF alpha's diverse biological roles.
Purpose of the Study:
- To identify signaling events specifically mediated by TNF-RII.
- To investigate the role of TRAF2 in TNF-RII signaling to MAP kinases.
- To differentiate TNF-RII signaling from TNF-RI pathways and cell death induction.
Main Methods:
- Construction of a chimeric receptor by fusing the CD4 extracellular domain to the TNF-RII intracellular domain.
- Activation of the chimeric receptor using anti-CD4 antibodies to isolate TNF-RII signaling.
- Analysis of MAP kinase activation (ERK, JNK) and NF-kappaB activation.
- Overexpression and dominant-negative inhibition of TRAF2.
Main Results:
- TNF-RII activation triggers the signaling of extracellular regulated kinase (ERK) and c-jun N-terminal kinase (JNK).
- TRAF2 overexpression is sufficient to activate JNK, and dominant-negative TRAF2 inhibits TNF alpha-induced JNK activation.
- TRAF2 mediates JNK and NF-kappaB activation through distinct signaling routes.
- TNF alpha-induced JNK activation in fibroblasts is independent of the apoptotic cell death pathway.
Conclusions:
- TNF-RII plays a significant role in activating MAP kinases, particularly JNK.
- TRAF2 is a critical mediator in the TNF receptor signaling cascade leading to JNK activation.
- TNF-RII signaling to JNK is separable from apoptotic pathways, highlighting TRAF2's specific role.