OBJECTIVE: TNFalpha plays a crucial role in rheumatoid arthritis (RA) by stimulating fibroblast-like synoviocytes (FLS). Lymphotoxin alpha (LTalpha) is a pro-inflammatory cytokine with significant homology to TNFalpha. We compared the effects of both cytokines on cultured RA FLS. METHODS: Receptor expression on RA FLS was analyzed by FACS. Cells were stimulated with LTalpha or TNFalpha and proliferation was measured by [3H]thymidine incorporation and secretion of inflammatory cytokines and metalloproteinase 3 by ELISA. Activation of MAP kinases and Akt was analyzed by Western blotting. Nuclear translocation of NFkappaB was visualized by immunofluorescence. RESULTS: 60-80% and 30-50% of the RA FLS tested expressed TNF receptors I and II, respectively, and 70-75% expressed HVEM. LTalpha induced RA FLS proliferation at the same level of TNFalpha, which was blocked by etanercept. Both LTalpha and TNFalpha induced activation of MAP kinases ERK1/2 and p38 as well as Akt. 95-98% of FLS showed nuclear translocation of NFkappaB after stimulation with either cytokines. LTalpha and TNFalpha were potent to induce secretion of IL-6, IL-8 and metalloproteinase 3 in FLS. CONCLUSION: LTalpha is as effective as TNFalpha in stimulating RA FLS. Blocking both cytokines might allow a better control of inflammation and synovial proliferation in RA.
Lymphotoxin alpha stimulates proliferation and pro-inflammatory cytokine secretion of rheumatoid arthritis synovial fibroblasts
Calmon-Hamaty, F.; Combe, B.; Hahne, M.; Morel, J.
2011-02 / vol 53 / pages 207-14
S1043-4666(10)00731-3 [pii] 10.1016/j.cyto.2010.10.010
1096-0023 (Electronic) 1043-4666 (Linking)
Humans; Cell Proliferation/drug effects; Protein Transport/drug effects; Arthritis, Rheumatoid/*pathology; Cell Nucleus/drug effects/metabolism; Cytokines/*secretion; Enzyme Activation/drug effects; Extracellular Signal-Regulated MAP Kinases/metabolism; Fibroblasts/drug effects/enzymology/pathology/*secretion; Immunoglobulin G/pharmacology; Inflammation Mediators/*metabolism; Lymphotoxin-alpha/*pharmacology; Matrix Metalloproteinase 3/secretion; NF-kappa B/metabolism; p38 Mitogen-Activated Protein Kinases/metabolism; Protein Kinase Inhibitors/pharmacology; Proto-Oncogene Proteins c-akt/metabolism; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Member 14/metabolism; Receptors, Tumor Necrosis Factor, Type I/metabolism; Receptors, Tumor Necrosis Factor, Type II/metabolism; Synovial Fluid/*cytology/drug effects