Loss of laminin and of the laminin receptor integrin subunit alpha 6 in situ correlates with cytokine induced down regulation of alpha 6 on fibroblast-like synoviocytes from rheumatoid arthritis

Abstract

Objective-To investigate in situ the expression of the integrin receptor subunits 6 and 1 and the distribution of the ligand laminin in the synovia from osteoarthritis (OA) and rheumatoid arthritis (RA) patients and to study the eVect of cytokines and antirheumatic drugs on the expression of the 6 and 1 integrin subunits on long term cultures of fibroblast-like synoviocytes (FBS) derived from OA and RA. Methods-The expression of the 6 and 1 integrin subunits and the distribution of laminin were examined immunohistochemically in normal synovia and in synovia from patients with OA and RA. The eVect of proinflammatory cytokines (IL1 and TNF ), and of antirheumatic drugs (salicylic acid, dexamethasone, and methotrexate) on the 6 and 1 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 6 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 6 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 6 integrin subunit. 1 was always strongly expressed in all synovia samples detected. Proinflammatory cytokines up regulated the expression of 6 and 1 on OA-FBS, whereas these eVectors decreased 6 and 1 on RA-FBS. In contrast, antirheumatic drugs, in particular methotrexate and dexamethasone, reduced the expression of 6 and 1 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 6 in SLC. IL1 and TNF down regulated the expression of the 6 and 1 integrin subunits on long term cultures of FBS derived from RA. Therefore, these cytokines may be among the eVectors regulating the expression of the 6 integrin subunit in SLC in vivo. As antirheumatic drugs increase the expression of 6 on RA-FBS, the presence of the laminin receptor may confer a protective eVect on the synovia in vivo. (Ann Rheum Dis 1998;57:559-565) Normal synovia is organised into an intimal layer of synovial lining cells and a subintima composed of fat and connective tissue that contains blood vessels and scattered leucocytes. Although, ultrastructurally no distinct basement membrane separates synovial lining cells (SLC) from the subintima, it has been shown immunhistochemically that diVerent extracellular matrix proteins like laminin, entactin, and collagen type IV present a defined distribution in the synovium.2 This network of extracellular matrix components might provide an anchoring basement membrane for the synovia. The structural organisation of the normal synovia is stabilised through cell-cell and cell-matrix interactions mediate...

Enhancement of Adenovirus-Mediated Gene Delivery to Rheumatoid Arthritis Synoviocytes and Synovium by Fiber Modifications: Role of Arginine-Glycine-Aspartic Acid (RGD)- and Non-RGD-Binding Integrins

“…This concept has been extended to disease-regulated therapeutic transgene expression (56 -58). Cytokines have been reported to downregulate ␣ v integrins in RA FLS and synovium (12,46). However, integrin expression levels do not correlate with Ad5-mediated transgene expression (13,59).…”

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Severe alterations in expression and localisation of 6 4 integrin in salivary gland acini from patients with Sjogren syndrome

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Gene Expression Profiling of Rheumatoid Arthritis Synovial Cells Treated with Antirheumatic Drugs

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