Tolllike receptors

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Toll-like receptors are a family of receptors that can respond to pathogens. They are ubiquitously expressed and have also been detected on cells found in the RA synovial joint in particular antigen presenting cells (APCs) and synovial fibroblast like cells [51-53]. TLRs recognise pathogen associated molecular patterns (PAMPs) (e.g., lipoproteins, lipopolysaccharide, unmethylated CpG, flagellin, dsRNA, etc.), but also have the capacity to recognise endogenous proteins and other molecules released during inflammation and cell death, such as HSP (heat shock protein) 70 and fibronectin.

TLRs signal by a similar signalling cascade to the IL-1R involving the adaptor protein myeloid differentiation protein 88 (MyD88) [54-56], IL-1-R-associated kinases (IRAK) 1, 2 and 4 [54, 55, 57] and TNF receptor-associated factor (TRAF) 6 [58] which activate inhibitor of NF-kB kinase (IKK) and the transcription factor nuclear factor kB (NF-kB). Many NF-KB-dependent genes are important in the inflammation associated with RA, and increased NF-kB activation has been observed in the rheumatoid synovium [59]. Evidence from MyD88 knockout mice indicated the existence of other adaptor molecules, as although some lipopolysac-

Figure 3

Hypothesis for TLR participation in inflammatory conditions such as rheumatoid arthritis a) Cells undergoing necrotic cell death due to tissue damage, releasing endogenous TLR lig-ands (e.g., heat shock proteins 60, 70 and gp 96) and/or breakdown of extracellular matrix (fibronectin fragments). Subsequently, macrophages are activated through TLR signalling and produce proinflammatory cytokines and chemokines which induce inflammation. b) Exogenous TLR ligands from bacterial or viral infection active macrophages through TLRs resulting in inflammation. c) The inflammation generated by endogenous and exogenous ligands cause cells to further tissue damage and release of endogenous TLR ligands.

Figure 3

Hypothesis for TLR participation in inflammatory conditions such as rheumatoid arthritis a) Cells undergoing necrotic cell death due to tissue damage, releasing endogenous TLR lig-ands (e.g., heat shock proteins 60, 70 and gp 96) and/or breakdown of extracellular matrix (fibronectin fragments). Subsequently, macrophages are activated through TLR signalling and produce proinflammatory cytokines and chemokines which induce inflammation. b) Exogenous TLR ligands from bacterial or viral infection active macrophages through TLRs resulting in inflammation. c) The inflammation generated by endogenous and exogenous ligands cause cells to further tissue damage and release of endogenous TLR ligands.

charide (LPS) responses were decreased in knockout mice, NF-kB activation was still observed [60]. The next TLR adaptor protein identified was MyD88 adaptorlike (Mal) protein [61] also termed TIR domain-containing adaptor protein (TIRAP) [62]. Two other adaptors Toll-interleukin-1 receptor domain containing adaptor inducing interferon-ß (TRIF) [63] also referred to as TICAM-1 [64], TRIF related adaptor molecule (TRAM) [65] also known as TIRP [66] or TICAM-2 [67] have been identified. They also activate NF-kB [63, 65, 67], along with interferon regulatory factor (IRF)-3 and IRF-7 [65, 68].

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Arthritis Relief and Prevention

Arthritis Relief and Prevention

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