Interleukin-1beta induces ICAM-1 expression enhancing leukocyte adhesion in human rheumatoid arthritis synovial fibroblasts: involvement of ERK, JNK, AP-1, and NF-kappaB.
Interleukin-1beta (IL-1beta) has been shown to induce the expression of adhesion molecules on various cell types and contributes to inflammatory responses. However, the molecular mechanisms by which IL-1beta induced intercellular adhesion molecule (ICAM)-1 expression remain unclear in human rheumatoid arthritis synovial fibroblasts (RASFs). Here, we demonstrated that IL-1beta induces ICAM-1 gene expression via the de novo protein synthesis through transcription and translation, which is attenuated by pretreatment with actinomycin D and cycloheximide, respectively. IL-1beta-induced ICAM-1 expression, extracellular signal-regulated kinase (ERK) and c-Jun-N-terminal kinase (JNK) phosphorylation, AP-1 activation, and nuclear factor-kappaB (NF-kappaB) p65 translocation were attenuated by the inhibitors of MEK1/2 (U0126), JNK (SP600125), AP-1 (tanshinone IIA), and NF-kappaB (helenalin) or transfection with respective short hairpin RNA plasmids. Moreover, IL-1beta-stimulated NF-kappaB p65 translocation was blocked by helenalin, but not by U0126 or SP600125, revealing that MAPKs and NF-kappaB pathways were independent on these responses. IL-1beta-stimulated AP-1 activation was blocked by U0126 or SP600125, revealing that ERK and JNK linked to AP-1 on these responses. IL-1beta-stimulated ICAM-1 gene expression was attenuated by pretreatment with U0126, SP600125, tanshinone IIA, or helenalin, revealed by ICAM-1 promoter assay and real-time RT-PCR analysis. Finally, up-regulation of ICAM-1 enhanced the adhesion of leukocytes to RASFs exposed to IL-1beta. These results suggest that in human RASFs, activation of ERK, JNK, AP-1, and NF-kappaB are essential for IL-1beta-induced ICAM-1 expression and leukocyte adhesion.
Yang
Chuen-Mao
CM
Department of Pharmacology, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan. chuenmao@mail.cgu.edu.tw
Luo
Shue-Fen
SF
Hsieh
Hsi-Lung
HL
Chi
Pei-Ling
PL
Lin
Chih-Chung
CC
Wu
Chi-Chuan
CC
Hsiao
Li-Der
LD
D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013583:Synovial Membrane / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D053583:Interleukin-1beta; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D018799:Intercellular Adhesion Molecule-1; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases