Disruption of CD40/CD40 ligand interaction with cleavage of CD40 on human gingival fibroblasts by human leukocyte elastase resulting in down-regulation of chemokine production.
CD40 is a crucial element in the process of fibroblast activation. We demonstrated that treatment of human gingival fibroblast (HGF) with human leukocyte elastase (HLE), a neutrophil serine protease, down-regulated the expression of CD40 and binding to the CD40 ligand (CD40L) using flow cytometry. The other neutrophil serine proteases, cathepsin G and proteinase 3, exhibited markedly less activity for CD40 reduction. The CD40 reduction by HLE was also observed in skin and lung fibroblasts, but not in monocytes, macrophages, and dendritic cells. The reduction resulted from direct proteolysis by HLE on the cell surface, because HLE reduced CD40 on fixed HGF and also on cell lysates and membranes. HLE treatment of HGF decreases interleukin (IL)-8 and macrophage chemoattractant protein-1 production by HGF when stimulated by CD40L, but not by IL-1alpha, suggesting that HLE inhibited a CD40-dependent cell activation. These results suggest that HLE possesses an anti-inflammatory effect for the HGF-mediated inflammatory process.
Nemoto
Eiji
E
Division of Periodontics and Endodontics, Tohoku University Graduate School of Dentistry, Sendai, Japan. eiji@mail.cc.tohoku.ac.jp
Tada
Hiroyuki
H
Shimauchi
Hidetoshi
H
D000293:Adolescent; D000328:Adult; D019013:CD40 Antigens / Q000096:biosynthesis / Q000502:physiology*; D023201:CD40 Ligand / Q000502:physiology*; D056649:Cathepsin G; D002403:Cathepsins / Q000494:pharmacology; D002478:Cells, Cultured / Q000187:drug effects; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D002648:Child; D003713:Dendritic Cells / Q000187:drug effects; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D000078404:Epidermal Cells; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D005881:Gingiva / Q000166:cytology*; D006801:Humans; D007249:Inflammation; D007375:Interleukin-1 / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D019272:Leukocyte Elastase / Q000494:pharmacology*; D008168:Lung / Q000166:cytology; D008264:Macrophages / Q000187:drug effects; D009000:Monocytes / Q000187:drug effects; D053146:Myeloblastin; D015260:Neprilysin / Q000378:metabolism; D009928:Organ Specificity; D011485:Protein Binding / Q000187:drug effects; D012697:Serine Endopeptidases / Q000494:pharmacology
D019013:CD40 Antigens; D018932:Chemokine CCL2; D007375:Interleukin-1; D016209:Interleukin-8; D023201:CD40 Ligand; D002403:Cathepsins; D018819:Dipeptidyl Peptidase 4; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; D019272:Leukocyte Elastase; D053146:Myeloblastin; D015260:Neprilysin