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Keywords:

  • BAFF;
  • inflammation;
  • IREM-1;
  • macrophage;
  • signalling transduction

Summary

The immune receptor expressed on myeloid cells 1 (IREM-1) has been known to regulate the activities of myeloid cells through its immunoreceptor tyrosine-based inhibition motifs (ITIMs) in its intracellular region. In order to investigate its effect on macrophage activation, a human macrophage cell line (THP-1) was tested after stimulation of its membrane-bound form of B cell activation factor (BAFF), which has been shown to modulate inflammatory activities through induction of proinflammatory mediator expression and suppression of phagocytosis. IREM-1-specific monoclonal antibodies detected the expression of high levels of IREM-1 in THP-1 cells. Cross-linking of IREM-1 with these antibodies resulted in the blockage of the BAFF-mediated expression of interleukin (IL)-8 and matrix metalloproteinase (MMP)-9 through inhibition of the activation of extracellular regulated kinase (ERK) and phosphorylation/degradation of IκB. Furthermore, cross-linking of IREM-1 also reversed the BAFF-mediated inhibition of phagocytosis. In order to demonstrate the role of ITIM in the IREM-1-mediated suppression of BAFF signalling, a decapeptide containing YADL (an ITIM in IREM-1) was fused with HIV–TAT48–57 which was required for the internalization of the synthetic polypeptide (TAT–YADL). TAT–YADL, but not control peptides, recapitulated the effect of the anti-IREM-1 monoclonal antibody. These observations indicate that IREM-1 exerted its inhibitory effect on BAFF-medicated signalling through ITIM-mediated regulation of ERK activities in THP-1 cells.