Immune response Toll-like receptor (TLR) ligands and common TLR signaling pathway leading to cell proinflammatory response

Toll-like receptor (TLR) ligands and common TLR signaling pathway leadingto cell proinflammatory response

Both gram-positive and gram-negative bacteria and their cell wall components activateinnate immune system of the host and induce secretion of proinflammatory molecules,mainly chemokines and cytokines [1]. Toll-like receptors (TLRs) initiatesignaling cascades through recognition of a variety of microbial components, thus servingas an important link between innate and adaptive immune responses. Each TLR recognizesdistinct ligands [2]. TLR2 agonists include peptidoglycan,lipoproteins, and lipopeptides from Gram-positive bacteria, mycobacteriallipoarabinomannan, mycoplasma lipopeptides [3], but only when present as aheterodimer in combination with either TLR1 or TLR6 [4].TLR3 and TLR5 mediate cell activation by double-stranded viral RNA andbacterial flagellin, respectively [3]. TLR9 responds to unmethylatedCpG motif in bacterial DNA [3], [4]. TLR4 is essentialin the respective recognition of lipopolysaccharide ( LPS ) [4],lipoteichoic acid [5] and some other substrates [6], [7], [8]. A number of microbial substrates are known for TLR7and TLR8 [9], [8],[10].

The main TLR-mediated immune response pathway, which is common for all TLRs, isMyeloid differentiation primary response gene 88 ( MyD88 )-dependent activation ofNuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor (NF-kB ) and c-Jun, transcription regulators of number of chemokines andcytokines responsible for cellular immune response. The main steps of NF-kBactivation involve MyD88/ Interleukin-1 receptor-associated kinases ( IRAK)/ TNF receptor-associated factor 6 ( TRAF6 )/ Mitogen-activated protein kinasekinase kinase 14 ( NIK )/ Inhibitor of kappa light polypeptide gene enhancer inB-cells ( IKK )/ NF-kB signal transduction [1]. C-Junactivation proceeds throw MyD88/ IRAK/ TRAF6/ Mitogen-activatedprotein kinase kinase kinase 7 interacting protein 1 ( TAB )/ Mitogen-activatedprotein kinase kinase kinase 7 ( TAK ) cascade [4], [11].Besides MyD88, some TLR s use alternative adaptor proteins to induceNF-kB and c-Jun activation, such as Toll-interleukin 1 receptor domaincontaining adaptor protein ( TIRAP ) [4], [12]. Certaintypes of TLRs (for example, TLR3 and TLR4 ) demonstrate also other responsepathways, which are specific for them.

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