title: Synthetic peptides containing ITIM-like sequences of IREM-1 inhibit BAFF-mediated regulation of interleukin-8 expression and phagocytosis through SHP-1 and/or PI3K.
abstract: B-cell activation factor of the tumour necrosis factor family (BAFF), an important regulator of B-cell survival, has recently been found to be expressed on the surface of murine and human macrophages and engagement with its receptor was shown to trigger induction of pro-inflammatory mediators and block phagocytic activity. In an effort to generate immunomodulatory agents that can regulate BAFF-mediated signal, decapeptides representing the intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs) of immune receptor expressed on myeloid cells (IREM)-1, an inhibitory transmembrane protein expressed on myeloid cells, were synthesized in conjugation with HIV-transactivator of transcription (TAT)(48-57,) which facilitates the internalization of peptides into cells. Interestingly, all five of these synthetic peptides, representing the five ITIM-like sequences present in the cytoplasmic tail of IREM-1, exhibited inhibitory action against BAFF-mediated induction of matrix metalloproteinase-9 and interleukin-8 expression. Inhibitor assay and immunoprecipitation assay followed by Western blotting demonstrated that the inhibitory action was mediated by Src homology 2 (SH2)-containing tyrosine phosphatase (SHP)-1 and/or phosphoinositide 3-kinase (PI3K). ELISA-based nuclear factor-κB DNA binding assay observed that the synthetic peptides blocked the activation of nuclear factor-κB in an SHP-1 and phosphoinositide 3-kinase-dependent manner. Three of these synthetic peptides exhibited varying degrees of inhibitory action against BAFF-mediated blockage of phagocytosis in a SHP-1 and PI3K-dependent manner. These data indicate that the synthetic peptides are capable of blocking BAFF-mediated regulation of macrophage activities through the activation of SHP-1 and PI3K as well as inhibition of nuclear factor-κB activation.
authors: School of Life Sciences and Biotechnology, Kyungpook National University, Daegu, Korea.
authors: Sang-Min
authors: SM
authors: Lee
authors: Eun-Ju
authors: EJ
authors: Kim
authors: Kyoungho
authors: K
authors: Suk
authors: Won-Ha
authors: WH
authors: Lee
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D053264:B-Cell Activating Factor / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D007155:Immunologic Factors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016209:Interleukin-8 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010587:Phagocytosis / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000737:chemistry / Q000378:metabolism*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000737:chemistry
chemical_list: D053264:B-Cell Activating Factor; C519443:CD300LF protein, human; D007155:Immunologic Factors; D016209:Interleukin-8; D016328:NF-kappa B; D009842:Oligopeptides; D011971:Receptors, Immunologic; C505719:TNFSF13B protein, human; D054322:tat Gene Products, Human Immunodeficiency Virus; D019869:Phosphatidylinositol 3-Kinases; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D020780:Matrix Metalloproteinase 9