Toll-like receptor signaling in cell proliferation and survival

Abstract

Toll-like receptors (TLRs) are important sensors of foreign microbial components as well as products of damaged or inflamed self tissues. Upon sensing these molecules, TLRs initiate a series of downstream signaling events that drive cellular responses including the production of cytokines, chemokines, and other inflammatory mediators. This outcome results from the intracellular assembly of protein complexes that drive phosphorylation and other signaling cascades ultimately leading to chromatin remodeling and transcription factor activation. In addition to driving inflammatory responses, TLRs also regulate cell proliferation and survival which serves to expand useful immune cells and integrate inflammatory responses and tissue repair processes. In this context, central TLR signaling molecules, such as the mitogen-activated protein kinases (MAPK) and phosphoinositide 3-kinase (PI3K), play key roles. In addition, four major groups of transcription factors which are targets of TLR activation also control cell fate. This review focuses on the role of TLR signaling as it relates to cell proliferation and survival. This topic not only has important implications for understanding host defense and tissue repair, but also cancer which is often associated with conditions of chronic inflammation.

Figure 1. MyD88 dependent and independent TLR signaling pathways

Activation of TLRs though ligand binding leads to the recruitment of the adaptor protein MyD88 or TRIF. In the MyD88 dependent pathway, activation of IRAK1 by IRAK4 leads to IRAK1 autophosphorylation which facilitates TRAF6 recruitment. TRAF6 then recruits MAP3Ks such as TAK1, MEKK2/3 and ASK1. TAK1 activation leads to the activation of IKK complex and the subsequent IkB degradation and NF-kB nucleus translocation. TAK1 also activates the p38-JNK signaling pathway. Tpl2, MEKK2/3 and ASK1 activate ERK1/2, p38-JNK and p38 respectively. In the MyD88-independent pathway TRIF activates TBK1 as well as IKKi which turns on the IRF-3 transcription factor. TRIF also activates NFkB signaling through RIP1. One of the most important consequences of TLR signaling is the transcriptional regulation of inflammatory genes as well as genes involved in cell proliferation and survival carried out by four groups of transcription factors.

Figure 2. PI3K pathway in TLR signaling

PI3K physically interacts with multiple TLRs as well as MyD88. Activated PI3K regulates TLR signaling in both positive and negative ways. Inactivation of GSK3 by PI3K-Akt enhances the transcription of IL10 by allowing CREB DNA binding as well as CREB-CBP association. IL-12 transcription is inhibited due to decreased association of NF-kB with CBP. PI3K-Akt also phosphorylates mTOR which leads to the phosphorylation and activation of IRF-7 as well as enhanced production of type I IFNs. PI3K-Akt pathway is also involved in cell proliferation or survival induced by multiple TLR ligands through degradation of the cell cycle inhibitor p27.

Figure 3. TLR signaling in cell proliferation and survival

TLR signaling engages two important adaptor proteins MyD88 and TRIF. MyD88 is required for the activation of downstream signaling pathways involving PI3K, MAP3Ks, IKK complex and FADD/caspases 8. PI3K activation leads to CREB activation and p27 degradation, both of which contribute to cell proliferation and/or survival. Activation of MAP3Ks induces the MAPK signaling cascades which eventually activate transcription factors including AP-1 and CREB. Activation of IKK complex results in NFkB nucleus translocation. All these three groups of transcription factors are engaged in the transcription of genes involved in cell fate control as well as inflammation. FADD/caspase8 is responsible for TLR2 induced apoptosis which is antagonized by NF-kB signaling. TRIF is involved in IRF-3 activation and the production of type I IFNs. IRF-3, 5 and 7 are all potential regulators of cell proliferation and survival.