The Potential of p38 MAPK Inhibitors to Modulate Periodontal Infections

Interestingly, the participation of at least four adaptor proteins containing Toll/IL-1 receptor (TIR) domains that can be recruited by activated TLRs results in important branching of the signal transduction and yields a significant flexibility to TLR signaling by allowing cross-talk with other pathways, including MAP kinase, PKR and Notch patways (). These adaptor proteins are recruited by TLRs by homophilic interactions between their TIR domains and are utilized differently by the TLRs. TLR5, TLR7 and TLR9 were shown to depend on recruitment of MyD88 to signal [, ], whereas TLR3 is the only TLR that does not use MyD88 []. TLR4, on the other hand, can use all four adaptor proteins: MyD88, TRIF, Mal/TIRAP and TRAM [-]. Even though activation of the canonical NF-κB pathway is usually effected by all TLRs, the timing of NF-κB activation [, ] as well as the additional signaling pathways that are activated by the branching of the signal varies among TLR receptors and with the participation of different adaptor proteins. These variations will ultimately affect the biological result in terms of gene expression and can provide opportunities for therapeutic manipulation of signaling by some of the pathways activated by cross-talk. This is demonstrated by the finding that even though NF-κB activation is observed after TLR4 stimulation by LPS, this may or may not result in inflammatory gene expression depending on the adaptor protein used. In wild-type cells, LPS stimulation results in inflammatory cytokine expression, whereas in MyD88-deficient cells LPS fails to induce cytokine expression. In the absence of MyD88, activation of NF-κB occurs with delayed kinetics in comparison to wild-type cells []. This delayed activation of NF-κB is dependent on TRIF, and interestingly both pathways involve activation of TRAF6/TAK1 which are common upstream activators of other signaling pathways such as MAP kinases.

Publication

The Potential of p38 MAPK Inhibitors to Modulate Periodontal Infections. () Keith L. Kirkwood, et al. Curr Drug Metab. ;10(1):55-67. Figure: F1. All organisms Homo sapiens Mus musculus Rattus norvegicus Canis lupus familiaris Drosophila melanogaster Danio rerio

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