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Involvement of MAPKs and NF-kappaB in tumor necrosis factor alpha-induced vascular cell adhesion molecule 1 expression in human rheumatoid arthritis synovial fibroblasts.
Arthritis Rheum. 2010 Jan; 62(1):105-16.AR

Abstract

OBJECTIVE

To investigate the roles of MAPKs and NF-kappaB in tumor necrosis factor alpha (TNFalpha)-induced expression of vascular cell adhesion molecule 1 (VCAM-1) in human rheumatoid arthritis synovial fibroblasts (RASFs).

METHODS

Human RASFs were isolated from synovial tissue obtained from patients with RA who underwent knee or hip surgery. The involvement of MAPKs and NF-kappaB in TNFalpha-induced VCAM-1 expression was investigated using pharmacologic inhibitors and transfection with short hairpin RNA (shRNA) and measured using Western blot, reverse transcriptase-polymerase chain reaction, and gene promoter assay. NF-kappaB translocation was determined by Western blot and immunofluorescence staining. The functional activity of VCAM-1 was evaluated by lymphocyte adhesion assay.

RESULTS

TNFalpha-induced VCAM-1 expression, phosphorylation of p42/p44 MAPK, p38 MAPK, and JNK, and translocation of NF-kappaB were attenuated by the inhibitors of MEK-1/2 (U0126), p38 (SB202190), JNK (SP600125), and NF-kappaB (helenalin) or by transfection with their respective shRNA. TNFalpha-stimulated translocation of NF-kappaB into the nucleus and NF-kappaB promoter activity were blocked by Bay11-7082, but not by U0126, SB202190, or SP600125. VCAM-1 promoter activity was enhanced by TNFalpha in RASFs transfected with VCAM-1-Luc, and this promoter activity was inhibited by Bay11-7082, U0126, SB202190, and SP600125. Moreover, up-regulation of VCAM-1 increased the adhesion of lymphocytes to the RASF monolayer, and this adhesion was attenuated by pretreatment with helenalin, U0126, SP600125, or SB202190 prior to exposure to TNFalpha or by anti-VCAM-1 antibody before the addition of lymphocytes.

CONCLUSION

In RASFs, TNFalpha-induced VCAM-1 expression is mediated through activation of the p42/p44 MAPK, p38 MAPK, JNK, and NF-kappaB pathways. These results provide new insights into the mechanisms underlying cytokine-initiated joint inflammation in RA and may inspire new targeted therapeutic approaches.

Authors+Show Affiliations

Chang Gung University, Chang Gung Memorial Hospital, Kwei-San, Tao-Yuan, Taiwan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20039412

Citation

Luo, Shue-Fen, et al. "Involvement of MAPKs and NF-kappaB in Tumor Necrosis Factor Alpha-induced Vascular Cell Adhesion Molecule 1 Expression in Human Rheumatoid Arthritis Synovial Fibroblasts." Arthritis and Rheumatism, vol. 62, no. 1, 2010, pp. 105-16.
Luo SF, Fang RY, Hsieh HL, et al. Involvement of MAPKs and NF-kappaB in tumor necrosis factor alpha-induced vascular cell adhesion molecule 1 expression in human rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 2010;62(1):105-16.
Luo, S. F., Fang, R. Y., Hsieh, H. L., Chi, P. L., Lin, C. C., Hsiao, L. D., Wu, C. C., Wang, J. S., & Yang, C. M. (2010). Involvement of MAPKs and NF-kappaB in tumor necrosis factor alpha-induced vascular cell adhesion molecule 1 expression in human rheumatoid arthritis synovial fibroblasts. Arthritis and Rheumatism, 62(1), 105-16. https://doi.org/10.1002/art.25060
Luo SF, et al. Involvement of MAPKs and NF-kappaB in Tumor Necrosis Factor Alpha-induced Vascular Cell Adhesion Molecule 1 Expression in Human Rheumatoid Arthritis Synovial Fibroblasts. Arthritis Rheum. 2010;62(1):105-16. PubMed PMID: 20039412.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Involvement of MAPKs and NF-kappaB in tumor necrosis factor alpha-induced vascular cell adhesion molecule 1 expression in human rheumatoid arthritis synovial fibroblasts. AU - Luo,Shue-Fen, AU - Fang,Rou-Yi, AU - Hsieh,Hsi-Lung, AU - Chi,Pei-Ling, AU - Lin,Chih-Chung, AU - Hsiao,Li-Der, AU - Wu,Chi-Chuan, AU - Wang,Jong-Shyan, AU - Yang,Chuen-Mao, PY - 2009/12/30/entrez PY - 2009/12/30/pubmed PY - 2010/3/12/medline SP - 105 EP - 16 JF - Arthritis and rheumatism JO - Arthritis Rheum VL - 62 IS - 1 N2 - OBJECTIVE: To investigate the roles of MAPKs and NF-kappaB in tumor necrosis factor alpha (TNFalpha)-induced expression of vascular cell adhesion molecule 1 (VCAM-1) in human rheumatoid arthritis synovial fibroblasts (RASFs). METHODS: Human RASFs were isolated from synovial tissue obtained from patients with RA who underwent knee or hip surgery. The involvement of MAPKs and NF-kappaB in TNFalpha-induced VCAM-1 expression was investigated using pharmacologic inhibitors and transfection with short hairpin RNA (shRNA) and measured using Western blot, reverse transcriptase-polymerase chain reaction, and gene promoter assay. NF-kappaB translocation was determined by Western blot and immunofluorescence staining. The functional activity of VCAM-1 was evaluated by lymphocyte adhesion assay. RESULTS: TNFalpha-induced VCAM-1 expression, phosphorylation of p42/p44 MAPK, p38 MAPK, and JNK, and translocation of NF-kappaB were attenuated by the inhibitors of MEK-1/2 (U0126), p38 (SB202190), JNK (SP600125), and NF-kappaB (helenalin) or by transfection with their respective shRNA. TNFalpha-stimulated translocation of NF-kappaB into the nucleus and NF-kappaB promoter activity were blocked by Bay11-7082, but not by U0126, SB202190, or SP600125. VCAM-1 promoter activity was enhanced by TNFalpha in RASFs transfected with VCAM-1-Luc, and this promoter activity was inhibited by Bay11-7082, U0126, SB202190, and SP600125. Moreover, up-regulation of VCAM-1 increased the adhesion of lymphocytes to the RASF monolayer, and this adhesion was attenuated by pretreatment with helenalin, U0126, SP600125, or SB202190 prior to exposure to TNFalpha or by anti-VCAM-1 antibody before the addition of lymphocytes. CONCLUSION: In RASFs, TNFalpha-induced VCAM-1 expression is mediated through activation of the p42/p44 MAPK, p38 MAPK, JNK, and NF-kappaB pathways. These results provide new insights into the mechanisms underlying cytokine-initiated joint inflammation in RA and may inspire new targeted therapeutic approaches. SN - 0004-3591 UR - https://www.unboundmedicine.com/medline/citation/20039412/Involvement_of_MAPKs_and_NF_kappaB_in_tumor_necrosis_factor_alpha_induced_vascular_cell_adhesion_molecule_1_expression_in_human_rheumatoid_arthritis_synovial_fibroblasts_ L2 - https://doi.org/10.1002/art.25060 DB - PRIME DP - Unbound Medicine ER -