Open Access

CD44 and Fas

  • Thomas Pap1
Arthritis Research & Therapy20013:70351

https://doi.org/10.1186/ar-2001-70351

Received: 9 August 2001

Accepted: 16 August 2001

Published: 16 August 2001

Keywords

Rheumatoid arthritis CD44 apoptosis Fas

Context

Apart from the increased expression of adhesion molecules and matrix-degrading enzymes, alterations in apoptosis are characteristic for rheumatoid arthritis synovial fibroblasts (RA-SFs). Recently, it has been shown that cross-linking of CD44 on RA-SFs triggers the upregulation of disease-relevant molecules such as vascular cell adhesion molecule (VCAM)-1. Also, inhibition of CD44 decreases the invasiveness of RA-SF into cartilage and reduces the severity of arthritis in animal models. The authors investigated the effects of CD44-mediated signalling on the expression of Fas, one major receptor involved in the induction of apoptosis. They also studied whether cross-linking of CD44 through specific antibodies or hyaluronan affects Fas-induced apoptosis in RA-SFs.

Significant findings

Cross-linking of CD44 on RA-SFs increased the transcription of Fas mRNA, as well as the surface expression of Fas. Maximum levels of Fas receptor were seen 3 hours after cross-linking of CD44, and Fas expression returned to the values for unstimulated cells after 24 hours. Stimulation with IL-1? or TNFa as well as cross-linking of MHC-I, intracellular adhesion molecule (ICAM)-1 or VCAM-1 had so significant effects on the expression of Fas. Cross-linking of CD44 on RA-SFs also increased the susceptibility of RA-SFs to apoptosis induced by monoclonal antibodies to Fas. Interestingly, stimulation with native hyaluronan did not result in a significant change in the amount of programmed cell death, whereas the fragmented 6.9-kDa form increased the rate of Fas-mediated apoptosis.

Comments

Although this paper does not necessarily demonstrate that "CD44 is the physiological trigger of Fas up-regulation ...", it provides a potential mechanism that helps to explain earlier findings showing an increased expression of Fas on RA-SFs. The authors propose that in the hyaluronan-rich environment of the rheumatoid synovium, CD44 upregulates Fas on RA-SFs and sensitises these cells to Fas-mediated apoptosis. It is also suggested that CD44 signalling is distinct from signalling pathways triggered by proinflammatory cytokines such as TNFa and Il-1?. These findings are of interest as they link the expression of CD44 to the apoptotic machinery in RA-SFs. However, the authors do not discuss recent observations indicating that the susceptibility to apoptosis is not increased in some RA-SFs despite their high expression of Fas (see Additional information). Therefore, further investigations will be needed to explain the resistance of RA-SFs to Fas-induced cell death in the context of CD44, proinflammatory cytokines and potential intrinsic factors.

Methods

Culture of synovial fibroblasts, in vitro stimulation, flow cytometry, northern blot

Additional information

Pap T, Muller-Ladner U, Gay RE, Gay S: Fibroblast biology. Role of synovial fibroblasts in the pathogenesis of rheumatoid arthritis. Arthritis Res 2000, 2:361-367 (PubMed abstract).

Authors’ Affiliations

(1)
University Hospital Magdeburg

References

  1. Fujii K, Fujii Y, Hubscher S, Tanaka Y: CD44 is the physiological trigger of Fas up-regulation on rheumatoid synovial cells. J Immunol. 2001, 167: 1198-1203.PubMedView ArticleGoogle Scholar

Copyright

© Biomed Central Ltd 2001

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