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.
OBJECTIVE
To investigate in situ the expression of the integrin receptor subunits alpha 6 and beta 1 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 alpha 6 and beta 1 integrin subunits on long term cultures of fibroblast-like synoviocytes (FBS) derived from OA and RA.


METHODS
The expression of the alpha 6 and beta 1 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 (IL1 beta and TNF alpha), and of antirheumatic drugs (salicylic acid, dexamethasone, and methotrexate) on the alpha 6 and beta 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 alpha 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 alpha 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 alpha 6 integrin subunit. beta 1 was always strongly expressed in all synovia samples detected. Proinflammatory cytokines up regulated the expression of alpha 6 and beta 1 on OA-FBS, whereas these effectors decreases alpha 6 and beta 1 on RA-FBS. In contrast, antirheumatic drugs, in particular methotrexate and dexamethasone, reduced the expression of alpha 6 and beta 1 on OA-FBS, whereas the same treatment on RA-FBS stimulated the expression of these integrin subunits.


CONCLUSIONS
The gradual loss of laminin in chronic synovitis may contribute to the altered expression of alpha 6 in SLC. IL1 beta and TNF alpha down regulated the expression of the alpha 6 and beta 1 integrin subunits on long term cultures of FBS derived from RA. Therefore, these cytokines may be among the effectors regulating the expression of the alpha 6 integrin subunit in SLC in vivo. As antirheumatic drugs increase the expression of alpha 6 on RA-FBS, the presence of the laminin receptor may confer a protective effect on the synovia in vivo.
Rinaldi
N
N
Department of Internal Medicine III, University of Ulm, Germany.
Barth
T F
TF
Weis
D
D
Schwarz-Eywill
M
M
Pezzutto
A
A
Lukoschek
M
M
Brocai
D
D
Brado
B
B
D015703:Antigens, CD / Q000187:drug effects / Q000378:metabolism*; D018501:Antirheumatic Agents / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D018929:Cell Culture Techniques; D016207:Cytokines / Q000494:pharmacology; D015536:Down-Regulation; D006801:Humans; D007124:Immunoenzyme Techniques; D039503:Integrin alpha6; D019012:Integrin beta1 / Q000187:drug effects / Q000378:metabolism; D016023:Integrins / Q000187:drug effects / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism*; D010003:Osteoarthritis / Q000378:metabolism / Q000473:pathology; D013583:Synovial Membrane / Q000378:metabolism*
D015703:Antigens, CD; D018501:Antirheumatic Agents; D016207:Cytokines; D039503:Integrin alpha6; D019012:Integrin beta1; D016023:Integrins; D007797:Laminin