Understanding the Role of Nf-Kappab Rela Subunit in Tlr and Rlr Pathways.

The innate immune system combats most threats of invading microorganisms successfully through specific recognition of pathogens by pattern recognition receptors, such as Toll-like receptors (TLRs) and retinoic-acid-inducible protein I-like receptors (RLRs). Pathogen-induced activation of these receptors activates transcription factor nuclear factor-kappaB (NF-kappaB), which plays an essential role in various immune responses. Mammalian NF-kappaB family has five members: RelA, RelB, cRel, p50 and p52. My thesis work studied the role of NF-kappaB subunit RelA in TLR and RLR pathways. Inflammatory responses, initiated by pro-inflammatory chemokines and cytokines, recruit phagocytes and effector molecules to sites of infection and prevent the spread of infection. Amongst key pro-inflammatory cytokines are TNF-alpha, interleukin (IL)-1 and IL-6. We have found that RelA, but not p50 and cRel, is specifically required for the induction of pro-inflammatory cytokines, including TNF-alpha, IL-1 and IL-6, by TLR4 pathway. My first study investigated the mechanisms of RelA requirement for the expression of pro-inflammatory cytokines. Focusing on IL-6, I found that the ability of RelA to specifically regulate IL-6 was not dependent on specific kappaB-site sequence or its unique ability to interact with the kappaB site. Instead, RelA interaction and synergism with coactivator CREB binding protein (CBP) determined RelA specificity. Together, our findings suggest an essential and specific role of RelA in TLR-induced inflammatory gene expression. Interferon-alpha/beta, which play a crucial role in anti-viral responses, are induced by RNA viruses in a cell-specific manner through the TLR and the RLR pathway. Although both pathways activate NF-kappaB, the role of NF-kappaB in anti-viral responses is not well studied. My second project examined the function of NF-kappaB, especially RelA, in antiviral responses. I found that RNA virus replication was increased in RelA deficient cells because RelA plays an important role in early IFN-beta expression after viral infection. RelA can synergize with low levels of interferon regulatory factor 3 and coactivator CBP to induce interferon-beta expression at early time after virus infection, which is crucial for controlling subsequent virus replication. Thus, these findings illustrate a novel and specific function of RelA in RLR-mediated anti-viral responses. In conclusion, my thesis work indicates unique and highly specific functions for RelA in both TLR and RLR pathways.