Lymphotoxin alpha stimulates proliferation and pro-inflammatory cytokine secretion of rheumatoid arthritis synovial fibroblasts

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.