Modulation of Tumor Necrosis Factor by Microbial Pathogens
Figure 1
TNF-Mediated Death and Survival Pathways
TNF-mediated death and survival pathways are activated following interaction with the TNFRs. The apoptotic pathway is activated through TNFR1 by forming the DISC, which activates caspase-8. Activated caspase-8 or −10 then activates the proapoptotic Bcl-2 family members, which leads to cell death by releasing cytochrome c from mitochondria and loss of MMP. The NF-κB-mediated survival pathway is activated by both TNFR1 and TNFR2. Association of TRAFs with these receptors activate signaling proteins like NIK (NF-κB inhibitor kinase) and MEKK1 (MAPK kinase 1), which activate the inhibitor of NF-κB (IkB) kinase (IKK) signalosome complex. IKK phosphorylates IkB, resulting in the degradation of the inhibitor. The free NF-κB than translocates to nucleus to induce the expression of inflammatory or antiapoptotic genes.