NF-kappaB-dependent lymphocyte hyperadhesiveness to synovial fibroblasts by hypoxia and reoxygenation: potential role in rheumatoid arthritis.
Hypoxia/reoxygenation has been incriminated as a major factor in the pathogenesis of ischemia/reperfusion injury in various ischemic diseases such as rheumatoid arthritis (RA). In this study, we have investigated the effect of hypoxia/reoxygenation on the expression of intercellular adhesion molecule-1 (ICAM-1) in synovial fibroblasts and adherence of lymphocytes to synovial fibroblasts. Hypoxia/reoxygenation strongly activated nuclear factor-kappaB (NF-kappaB) in synovial fibroblasts to the levels produced by phorbol 12-myristate 13-acetate and caused lymphocyte hyperadhesiveness to synovial fibroblasts as well as up-regulation of ICAM-1, both of which were completely blocked by a NF-kappaB antagonist (pyrrolidine dithiocarbamate). These results indicate that hypoxia/reoxygenation has a major role in sequestration of inflammatory cells to synovium mediated by the activation of NF-kappaB. Our data suggest that hypoxia/reoxygenation could be an important target for the development of new, therapeutic strategies in RA.
Han
Myung-Kwan
MK
Department of Microbiology, Chonbuk National University Medical School, Chonju, Korea.
Kim
Jong-Suk
JS
Park
Byung-Hyun
BH
Kim
Jung-Ryul
JR
Hwang
Byung-Yun
BY
Lee
Hak-Yong
HY
Song
Eun-Kyung
EK
Yoo
Wan-Hee
WH
D000975:Antioxidants / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D015153:Blotting, Western; D002273:Carcinogens / Q000494:pharmacology; D002448:Cell Adhesion / Q000502:physiology; D002478:Cells, Cultured; D017931:DNA Primers / Q000737:chemistry; D005347:Fibroblasts / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013583:Synovial Membrane / Q000166:cytology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology; D015854:Up-Regulation
D000975:Antioxidants; D002273:Carcinogens; D017931:DNA Primers; D016328:NF-kappa B; D011759:Pyrrolidines; D012333:RNA, Messenger; D013859:Thiocarbamates; D018799:Intercellular Adhesion Molecule-1; C020972:pyrrolidine dithiocarbamic acid; D013755:Tetradecanoylphorbol Acetate; D010100:Oxygen