Proposed model for the action of lymphotoxin alpha (LTα) in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLSs). RA FLSs express all LTα receptors (TNFR1, TNFR2, and HVEM). TNFR1 contains a cytoplasmic death domain (DD). Although the specific contribution of each receptor for LTα signaling remains to be clarified, RA FLSs are activated upon LTα binding through the phosphorylation of the mitogen-activated protein kinases p38 and ERK1/2 and of the phosphatidylinositol 3-kinase (PI3K) Akt. Transcription factors such as nuclear factor-kappa-B (NF-κB), in turn, are activated. These events lead to cell responses involved in the pathogenesis of RA, such as proliferation, survival, and secretion of proinflammatory cytokines, chemokines, and matrix metalloproteinases (MMPs). Based on . ERK, extracellular signal-regulated kinase; HVEM, herpesvirus entry mediator; IL, interleukin; JNK, c-jun N-terminal kinase; RANTES, regulated upon activation, normal T cell expressed and secreted; TNFR, tumor necrosis factor receptor.
Calmon-Hamaty et al. Arthritis Research & Therapy 2011 13:232 doi:10.1186/ar3376