TLR-4, IL-1R and TNF-R signaling to NF-κB: variations on a common theme

Abstract

Abstract. Toll-like receptors (TLRs) as well as the receptors for tumor necrosis factor (TNF-R) and interleukin-1 (IL-1R) play an important role in innate immunity by regulating the activity of distinct transcription factors such as nuclear factor-kB (NF-kB). TLR, IL-1R and TNF-R signaling to NF-kB converge on a common IkB kinase complex that phosphorylates the NF-kB inhibitory protein IkBa. However, upstream signaling components are in large part receptor-specific. Nevertheless, the principles of signaling are similar, involving the recruitment of specific adaptor proteins and the activation of kinase cascades in which protein-protein interactions are controlled by poly-ubiquitination. In this review, we will discuss our current knowledge of NF-kB signaling in response to TLR-4, TNF-R and IL-1R stimulation, with a special focus on the similarities and dissimilarities among these pathways.Keywords. Toll-like receptor 4, interleukin-1, tumor necrosis factor, NF-kB, signal transduction. NF-kB, does it still need to be introduced?Nuclear factor kB (NF-kB) is the generic name of a family of transcription factors that regulate the expression of a large number of genes involved in immune and inflammatory responses, as well as in cell survival, cell proliferation and cell differentiation. NFkB transcription factors are activated in response to various stimuli, including cytokines, infectious agents, injury and other stressful conditions requiring rapid reprogramming of gene expression. Inappropriate activation of the NF-kB signaling pathway is implicated in the pathogenesis of chronic inflammation and autoimmunity, certain hereditary disorders and various cancers. In mammals, the NF-kB family consists of five proteins sharing a highly conserved Rel homology domain: c-Rel, RelB, p65 (= RelA), p105 (= NF-kB1) and p100 (=NF-kB2). The first three contain Cterminal transactivation domains, while the others share a long C-terminal domain with multiple copies of ankyrin repeats, which inhibit their activation.

Outer Membrane Protein A (OmpA) of Shigella flexneri 2a Links Innate and Adaptive Immunity in a TLR2-dependent Manner and Involvement of IL-12 and Nitric Oxide

“…These observations signify that OmpA is capable of inducing PKC␣ activation and secretion of NO by macrophages abso-lutely in a TLR2-dependent manner. TLRs play a crucial role in innate immune responses with the secretion of NO, and different cytokines and chemokines, which involve participation of many intracellular signaling molecules (30,31) …”

Interleukins 1α and 1β secreted by some melanoma cell lines strongly reduce expression of MITF‐M and melanocyte differentiation antigens

“…21 Given the overlap in signaling pathways used by TNF-a and IL-1 cytokines (reviewed in Ref. 41 ), we suggest that NF-jB and JNK are important mediators in the observed downregulation of differentiation genes in melanoma cells incubated with these inflammatory cytokines. Detailed signaling mechanisms should, therefore, be explored further.…”

Autophagy Suppresses Interleukin-1β (IL-1β) Signaling by Activation of p62 Degradation via Lysosomal and Proteasomal Pathways

“…The fact that both NF-B and MAPK pathways are affected by ATG16L1 deletion indicated that its regulation of IL-1␤ signaling by ATG16L1 must be at or above the divergence of both pathways, such as at the level of MyD88-IRAK-TRAF6-TAK1 (17). We therefore searched for molecules that are affected by ATG16L1 and influence the MyD88-IRAK-TRAF6-TAK1 activation.…”