Signal Transduction

FIG 15.11  Negative feedback of the TLR4 signal transduction pathways: resolution of the inflammatory response.

Among the genes regulated by the different transcription factors are proteases that cleave the ubiquitin isopeptide bonds. Their action causes disassembly of the TRAF6-mediated signalling complexes. Activated p38 phosphorylates the ubiquitin binding protein TAB2 as well as the regulatory subunit TAB1. Both phosphorylations cause inactivation of TAK1. ATF3 is also one of the targets of the TLR4 signal pathways, acting to suppress transcription of IL-6 and IL-12 when bound to NF- B and ATF2/c-Jun. Finally, IL-10 has a general inhibitory effect on expression of pro-inflammatory cytokines. Collectively, these negative feedback pathways act to resolve the inflammatory response. Compare with Figure 15.5 (1aar70).

Negative feedback control of the TLR4 pathway

We present four ways by which the TLR4 pathway is held in check. These either involve an activated protein kinase that feeds back on upstream components or involve gene products that are induced by the TLR4 pathway (see Figure 15.11).

1.The transcription factor ATF3 participates in the same transcription complex as NF- B and ATF2, acting as a negative regulator of IL-6 and IL-12. It does this by altering the chromatin structure, thereby restricting access to the other transcription factors.65

2.Inhibition of TAK1 by phosphorylation of its regulators TAB1 and TAB2 (or TAB3) by p38 (see Figure 15.6).66

3.Expression of de-ubiquitylating enzymes which break the K63-peptide bond in TRAF6.67,68

4.Expression of the cytokine IL-10 which terminates the inflammatory response by deactivating macrophages and effector T cells and silencing the synthesis of TNF- , IL-6, IL-1 , and an array of chemokines.69

Some consequences of TLR4-induced gene transcription

Below we list some of the mediators generated following provocation by foreign organisms and activation of pattern recognition receptors (PRR, see page

452). Although many cells contribute to mediator production and therefore

466