title: SHPS-1 and a synthetic peptide representing its ITIM inhibit the MyD88, but not TRIF, pathway of TLR signaling through activation of SHP and PI3K in THP-1 cells.
abstract: BACKGROUND
  Src homology 2 domain-containing protein tyrosine phosphatase substrate (SHPS)-1 is known to have regulatory effects on myeloid cells. However, its role in macrophage activation is not clearly understood.
  
  
  RESULTS
  In order to investigate the role of SHPS-1 in Toll-like receptor (TLR)-mediated activation, human monocytic cell lines were treated with anti-SHPS-1 monoclonal antibody. The triggering of SHPS-1 blocked the expression of IL-8 and TNF-α in cells treated with a TLR4 ligand that induces a signaling pathway involving myeloid differentiation factor 88 (MyD88) and Toll-interleukin-1 receptor (TIR)-domain-containing adapter-inducing interferon-β (TRIF). Interestingly, SHPS-1 inhibited TLR9/MyD88-mediated, but not TLR3/TRIF-mediated, expression of IL-8. Accordingly, a synthetic peptide representing the immunoreceptor tyrosine-based inhibition motif (ITIM) of SHPS-1 suppressed only the MyD88 pathway. Utilization of specific inhibitors and Western blot analysis indicated that the inhibitory effects were mediated by Src homology 2 domain-containing phosphatases (SHPs) and phosphoinositide 3-kinase (PI3K).
  
  
  CONCLUSIONS
  SHPS-1 negatively regulates the MyD88-dependent TLR signaling pathway through the inhibition of NF-κB activation.
authors: School of Life Sciences and Biotechnology, Kyungpook National University, Daegu 702-701, Korea.
authors: Eun-Ju
authors: EJ
authors: Kim
authors: Kyoungho
authors: K
authors: Suk
authors: Won-Ha
authors: WH
authors: Lee
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000943:Antigens, Differentiation / Q000378:metabolism*; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D006801:Humans; D061626:Immunoreceptor Tyrosine-Based Inhibition Motif; D016209:Interleukin-8 / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000943:Antigens, Differentiation; D016209:Interleukin-8; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D010455:Peptides; D011971:Receptors, Immunologic; C501920:SIRPA protein, human; C470409:TICAM1 protein, human; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; C516724:PTPN11 protein, human; C509249:PTPN6 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6