title: Proinflammatory activity of TWEAK on human dermal fibroblasts and synoviocytes: blocking and enhancing effects of anti-TWEAK monoclonal antibodies.
abstract: Human tumour necrosis factor (TNF)-like weak inducer of apoptosis (hTWEAK) and two anti-hTWEAK mAbs were tested for their ability to elicit or block inflammatory responses in cultured human dermal fibroblasts and synoviocytes. Incubation with hTWEAK increased the production of prostaglandin E2, matrix metalloproteinase-1 (MMP-1), IL-6, and the chemokines IL-8, RANTES (regulated on activation, normal T expressed and secreted) and interferon-gamma-inducible protein-10 (IP-10) in culture supernatant of fibroblasts and synoviocytes. In combination with TNF or IL-1beta, hTWEAK further stimulated the secretion of prostaglandin E2, MMP-1, IL-6 and IL-8 up to fourfold, and IP-10 and RANTES up to 70-fold compared to TNF or IL-1beta alone. An anti-hTWEAK mAb, BCB10, blocked the effects of hTWEAK, whereas hTWEAK crosslinked by the anti-hTWEAK mAb, BEB3, further stimulated the inflammatory response of fibroblasts and synoviocytes. The anti-hTWEAK mAbs were ineffective in blocking or increasing the responses of TNF or IL-1beta and blocking anti-TNF mAb was ineffective in preventing the responses to TWEAK. These results were also confirmed at the RNA level for MMP-1, macrophage chemoattractant protein-1, RANTES, macrophage inflammatory protein-1alpha, IP-10 and IL-8. TWEAK in synergism with IL-1 and TNF may be an additional cytokine that plays a role in destructive chronic arthritic diseases.
authors.affiliation: CyGen, Carouge, Switzerland.
authors.forename: Yves
authors.initials: Y
authors.lastname: Chicheportiche
authors.forename: Rachel
authors.initials: R
authors.lastname: Chicheportiche
authors.forename: Irene
authors.initials: I
authors.lastname: Sizing
authors.forename: Jeff
authors.initials: J
authors.lastname: Thompson
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Benjamin
authors.forename: Christine
authors.initials: C
authors.lastname: Ambrose
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Dayer
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000276:immunology / Q000494:pharmacology*; D018925:Chemokines / Q000378:metabolism*; D000074049:Cytokine TWEAK; D020405:Dermis / Q000166:cytology* / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins; D013583:Synovial Membrane / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D048069:Tumor Necrosis Factors
chemical_list: D000911:Antibodies, Monoclonal; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D018925:Chemokines; D000074049:Cytokine TWEAK; D004338:Drug Combinations; D012333:RNA, Messenger; D011994:Recombinant Proteins; C109743:TNFSF12 protein, human; D048069:Tumor Necrosis Factors; D020781:Matrix Metalloproteinase 1; D015232:Dinoprostone