Loss of laminin and of the laminin receptor integrin subunit α6 in situ correlates with cytokine induced down regulation of α6 on fibroblast-like synoviocytes from rheumatoid arthritis

Abstract

Objective - To investigate in situ the expression of the integrin receptor subunits α6 and β1 and the distribution of the ligand laminin in the synovia from osteoarthritis (OA) and rheumatoid arthritis (RA) patients and to study the effect of cytokines and antirheumatic drugs on the expression of the α6 and β1 integrin subunits on long term cultures of fibroblast-like synoviocytes (FBS) derived from OA and RA. Methods - The expression of the α6 and β1 integrin subunits and the distribution of laminin were examined immunohistochemically in normal synovia and in synovia from patients with OA and RA. The effect of proinflammatory cytokines (IL1β and TNFα), and of antirheumatic drugs (salicylic acid, dexamethasone, and methotrexate) on the α6 and β1 expression of cultured normal FBS and FBS from patients with OA and RA was determined by flow cytometry. Results - In normal synovia and in OA synovia samples with a low grade of inflammation, synovial lining cells (SLC) showed a parallel expression and distribution of α6 and laminin. In synovia samples of OA with a higher grade of inflammation and in the majority of RA synovia samples laminin was pericellularly distributed in a low number of SLC, whereas α6 was expressed on the surface of a high number of SLC. In RA synovia samples with severe inflammatory changes the gradual loss of laminin generally corresponded to a decrease of the α6 integrin subunit. β1 was always strongly expressed in all synovia samples detected. Proinflammatory cytokines up regulated the expression of α6 and β1 on OA-FBS, whereas these effectors decreased α6 and β1 on RA- FBS. In contrast, antirheumatic drugs, in particular methotrexate and dexamethasone, reduced the expression of α6 and β1 on OA-FBS, whereas the same treatment on RA-FBS stimulated the expression of these integrin subunits. Conclusion - The gradual loss of laminin in chronic synovitis may contribute to the altered expression of α6 in SLC. IL1β and TNFα down regulated the expression of the α6 and β1 integrin subunits on long term cultures of FBS derived from RA. Therefore, these cytokines may be among the effectors regulating the expression of the α6 integrin subunit in SLC in vivo. As antirheumatic drugs increase the expression of α6 on RA-FBS, the presence of the laminin receptor may confer a protective effect on the synovia in vivo.