title: Human β Defensin-3 Increases CD86 Expression on Monocytes by Activating the ATP-Gated Channel P2X7.
abstract: Human β defensin-3 (hBD-3), an epithelial cell-derived antimicrobial peptide, mediates chemotaxis and activation of myeloid cells. In this study, we provide evidence that hBD-3 induces the costimulatory molecule CD86 on primary human monocytes by a mechanism involving autocrine activation of ionotropic P2X7 receptors (P2X7R) by ATP. Incubation of monocytes with hBD-3 resulted in increased expression of both the CD80 and CD86 costimulatory molecules. Treatment of monocytes with a selective P2X7R antagonist inhibited the ability of hBD-3 to induce expression of CD86 but not CD80. The hBD-3-dependent upregulation of CD86 was also attenuated in monocytes incubated with apyrase, a potent scavenger of extracellular ATP. Finally, direct activation of monocyte P2X7R by exogenous ATP mimicked the ability of hBD-3 to induce CD86 expression. These data suggest that hBD-3 induces monocyte activation by both P2X7-dependent (CD86 upregulation) and P2X7-independent (CD80 upregulation) signaling mechanisms and raise the possibility that activation of P2X7R could play an important role in shaping the inflammatory microenvironment in conditions where hBD-3 is highly expressed, such as psoriasis or oral carcinoma.
authors.affiliation: Department of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, OH 44106;
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Lioi
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Center for AIDS Research, Case Western Reserve University, Cleveland, OH 44106;
authors.forename: Brian M
authors.initials: BM
authors.lastname: Ferrari
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106; and.
authors.forename: George R
authors.initials: GR
authors.lastname: Dubyak
authors.affiliation: Department of Biological Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, OH 44106.
authors.forename: Aaron
authors.initials: A
authors.lastname: Weinberg
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Center for AIDS Research, Case Western Reserve University, Cleveland, OH 44106; scott.sieg@case.edu.
authors.forename: Scott F
authors.initials: SF
authors.lastname: Sieg
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology*; D001081:Apyrase / Q000378:metabolism / Q000494:pharmacology; D018122:B7-1 Antigen / Q000235:genetics / Q000378:metabolism; D051940:B7-2 Antigen / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D023083:beta-Defensins / Q000494:pharmacology*
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; C422950:DEFB103A protein, human; D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7; D023083:beta-Defensins; D000255:Adenosine Triphosphate; D001081:Apyrase; D002118:Calcium