Étude des effets anti-cytokines et anti-cataboliques des rétinoïdes sur les fibroblastes synoviaux et les chondrocytes de rat ou humains stimulés par de l'Interleukine-1 Bêta

Abstract : Retinoids (molecules derivated from vitamin A) used in experimental models of arthropathies, have shown interesting anti-arthritic properties. We have studied retinoid effects on the inhibition of pro-inflammatory cytokines and matrix metalloproteases (MMP) induced by IL-1b in rat and human synovial fibroblasts and chondrocytes. In pro-inflammatory conditions, synovial fibroblasts produce large quantities of inflammatory cytokines in the joint (TNF-a, IL-1b, IL-6). Both all-trans retinoic acid (ATRA, agonist of RAR) and 9-cis retinoic acid (9-cis RA, co-agonist of RAR and RXR) inhibit the expression of these cytokines in rat synovial fibroblasts stimulated by IL-1. ATRA also inhibit the phosphorylation of ERK1/2 induced by IL-1, without affecting that of p38 or JNK, and decrease activation of transcription factors AP-1, NF-kB and NF-IL-6 induced by IL-1. The effect of ATRA on inflammatory cytokines expression is not potentiated by RXR agonist, nor reproduces by selective RAR agonists, and is not antagonized by RAR isotypes silencing, showing that the effects of ATRA are independent of RAR or RXR. However, the inhibitory effect of ATRA on AP-1 and on NF-IL-6 is reproduced by a ERK1/2 antagonist. In pro-inflammatory conditions, chondrocytes produce large amounts of MMP and nitrites. ATRA inhibits iNOS expression and nitrites production induced by IL-1 in rat and human chondrocytes. However, total MMP activity is only inhibited in human chondrocytes, and this difference is not the consequence of a variable modulation of AP-1 activation. These results showed that retinoids have an important impact on inflammatory parameters on articular cells, but they varied regarding to the species, suggesting that extrapolation of results obtained from rat cells to human is difficult.
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Mélanie Kirchmeyer. Étude des effets anti-cytokines et anti-cataboliques des rétinoïdes sur les fibroblastes synoviaux et les chondrocytes de rat ou humains stimulés par de l'Interleukine-1 Bêta. Médecine humaine et pathologie. Université Henri Poincaré - Nancy 1, 2008. Français. ⟨NNT : 2008NAN10137⟩. ⟨tel-01777276⟩

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