title: Synthetic peptides containing ITIM-like sequences of IREM-1 (CD300F) differentially regulate MyD88 and TRIF-mediated TLR signalling through activation of SHP and/or PI3K.
abstract: The immune receptor expressed on myeloid cells 1 (IREM-1/CD300F) has been shown to inhibit various inflammatory processes in myeloid cells, such as macrophages and mast cells. IREM-1 exerts its inhibitory effect through its intracellular immunoreceptor tyrosine-based inhibition motifs (ITIMs). In order to generate immunomodulatory molecules that can regulate the inflammatory activation of macrophages, decapeptides representing each of the five ITIM-like sequences in the cytoplasmic tail of IREM-1 were synthesized in conjugation with human immunodeficiency virus-transactivator of transcription (HIV-TAT(48-57)), which was added to promote internalization of the peptides. Interestingly, all these TAT-ITIM fusion peptides inhibited Toll-like receptor (TLR)-mediated production of proinflammatory molecules, including matrix metalloproteinase (MMP)-9, tumour necrosis factor (TNF)-α, monocyte chemotactic protein-1 (MCP-1) and interleukin (IL)-8. When various TLR ligands were used to stimulate the human macrophage-like cell line human acute monocytic leukaemia cell line (THP)-1, the TAT-ITIM peptides blocked both myeloid differentiation factor 88 (MyD88) and Toll-interleukin 1 receptor (TIR)-domain-containing adapter-inducing interferon-β (TRIF)-mediated TLR signalling pathways. Utilization of specific inhibitors and detection of the active form of signalling adaptors by Western blot analysis further demonstrated that the inhibitory effects of these TAT-ITIM peptides require activation of Src homology 2 (SH2)-containing tyrosine phosphatase (SHP) and/or phosphoinositide 3-kinase (PI3K). These data indicate that these synthetic peptides may be used to regulate immune responses that involve TLR-mediated inflammatory activation of macrophages.
authors.affiliation: School of Life Sciences and Biotechnology, Kyungpook National University, Daegu, Korea.
authors.forename: S-M
authors.initials: SM
authors.lastname: Lee
authors.forename: K
authors.initials: K
authors.lastname: Suk
authors.forename: W-H
authors.initials: WH
authors.lastname: Lee
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology*; D000595:Amino Acid Sequence; D002460:Cell Line; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D008969:Molecular Sequence Data; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000276:immunology; 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 / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics / Q000276:immunology
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C519443:CD300LF protein, human; C508606:CXCL8 protein, human; D016209:Interleukin-8; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D010446:Peptide Fragments; D011971:Receptors, Immunologic; C470409:TICAM1 protein, human; D051193:Toll-Like Receptors; D054322:tat Gene Products, Human Immunodeficiency Virus; C520542:tat peptide (48-57), Human immunodeficiency virus 1; 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; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D020780:Matrix Metalloproteinase 9