Pattern recognition receptors and innate immune signaling. TLR-2, TLR-4, and TLR-9 are depicted as examples of TLR receptors expressed in cells of the periodontal tissues. Upon ligand binding, all TLRs (except TLR3) recruit adaptor protein MyD88 and activate common upstream activator (IRAK/TRAF6 and TAK1) of NF-kB and MAP kinases. TLR-4 may also activate NF-kB independent of MyD88 and with delayed kinetics (red dotted line). Nod1/Nod2 are cytosolic PRRs that recognize peptidoglycan fragments of the bacterial wall and may amplify TLR-induced activation of signaling pathways. Activated NF-kB and MAP kinases translocate to the nucleus and bind to their motifs (NF-kB, AP-1, resp.) in the promoter of target genes (including early-response and inflammatory genes) and induce their transcription into mRNA which will ultimately lead to increased cytokine production. p38 MAP kinase also involved posttranscriptional regulation of pro-inflammatory genes (for example, IL-6, Cox-2) by modulation of mRNA stability in the cytoplasm. (TLR: toll-like receptor, CD14: cluster of differentiation 14 molecule; MD2: myeloid differentiation protein 2; MyD88: myeloid differentiation primary response gene 88; IRAK: interleukin-1 receptor-associated kinase; TRAF6: TNF receptor associated factor 6; TAK1: TGF-beta activated kinase 1; MKK: mitogen-activated protein kinase kinase; ERK: extracellular signal-regulated kinase: JNK: c-Jun N-terminal kinase; AP-1: activator protein-1).
