title: Proinflammatory effects of tumour necrosis factor-like weak inducer of apoptosis (TWEAK) on human gingival fibroblasts.
abstract: Tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK), a member of the TNF family, is a multi-functional cytokine that regulates cellular proliferation, angiogenesis, inflammation and apoptosis. In this study, we investigated TWEAK expression in periodontally diseased tissues and the effect of TWEAK on human gingival fibroblasts (HGF). Reverse transcription-polymerase chain reaction (RT-PCR) analysis and immunohistochemistry revealed that TWEAK and the TWEAK receptor, fibroblast growth factor-inducible 14 (Fn14), mRNA and protein were expressed in periodontally diseased tissues. HGF expressed Fn14 and produced interleukin (IL)-8 and vascular endothelial growth factor (VEGF) production upon TWEAK stimulation in a dose-dependent manner. The IL-8 and VEGF production induced by TWEAK was augmented synergistically by simultaneous stimulation with transforming growth factor (TGF)-beta1 or IL-1beta. IL-1beta and TGF-beta1 enhanced Fn14 expression in a dose-dependent manner. Moreover, TWEAK induced intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression on HGF in a dose-dependent manner. The ICAM-1 expression induced by TWEAK was augmented by TGF-beta1. On the other hand, the TWEAK-induced VCAM-1 expression was inhibited by TGF-beta1. Phosphatidylinositol 3-kinase (PI3K) and nuclear factor-kappaB (NF-kappaB) inhibitor inhibit both ICAM-1 and VCAM-1 expression induced by TWEAK. However, mitogen-activated protein kinase (MEK) and c-Jun NH2-terminal kinase (JNK) inhibitor enhanced only VCAM-1 expression on HGF. These results suggest that TWEAK may be involved in the pathophysiology of periodontal disease. Moreover, in combination with IL-1beta or TGF-beta1, TWEAK may be related to the exacerbation of periodontal disease to induce proinflammatory cytokines and adherent molecules by HGF.
authors.affiliation: Department of Conservative Dentistry and Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Tokushima, Japan. hosokawa@dent.tokushima-u.ac.jp
authors.forename: Y
authors.initials: Y
authors.lastname: Hosokawa
authors.forename: I
authors.initials: I
authors.lastname: Hosokawa
authors.forename: K
authors.initials: K
authors.lastname: Ozaki
authors.forename: H
authors.initials: H
authors.lastname: Nakae
authors.forename: T
authors.initials: T
authors.lastname: Matsuo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000276:immunology; D002478:Cells, Cultured; D000074049:Cytokine TWEAK; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D005347:Fibroblasts / Q000276:immunology*; D015870:Gene Expression; D005881:Gingiva / Q000276:immunology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology; D016209:Interleukin-8 / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D010518:Periodontitis / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000276:immunology; D000074050:TWEAK Receptor; D053773:Transforming Growth Factor beta1 / Q000276:immunology; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D000074049:Cytokine TWEAK; D053583:Interleukin-1beta; D016209:Interleukin-8; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; D053773:Transforming Growth Factor beta1; D048069:Tumor Necrosis Factors; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; D018799:Intercellular Adhesion Molecule-1