| dc.description.abstract | Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disease. It targets multiple joints with complex pathological processes. To date, the etiology of RA is not fully understood. Accumulating evidence indicates that cAMP-elevating agents can negatively modulate many inflammatory responses in virtually all immune inflammatory cells and thereby ameliorate inflammatory diseases. Type 4 phosphodieasterases (PDE4s) are the predominant cAMP-hydrolyzing enzymes in most immune cells, hence being important in controlling the intracellular cAMP concentration and immune functions. So far, the PDE4 inhibitors Roflumilast and Apremilast are used in clinic to treat chronic obstructive pulmonary disease (COPD) and psoriasis and psoriatic arthritis, respectively. Using the animal models of RA, several studies have shown that the incidence and severity of arthritis as well as articular pannus formation and cartilage damage are significantly reduced by PDE4 inhibitors in experimantal animals. However, the molecular mechanisms of these effects still remain unclear. It is known that the helper Th1 and Th17 cells are involved in the pathogenesis of RA by secreting the cytokines IFN-γ and IL-17A, respectively. Thus, in this study we used collagen-induced arthritis (CIA) model to determine whether inhibition of PDE4 can regulate the IFN-γ and IL-17A release as well as the arthritic severity in CIA mice. Using type II collagen (CII) to immunize DBA/1 mice by two protocols (i.e., i.d./i.d. and i.d./i.p. models), we first observed that CII-induced IFN-γ and IL-17A release in local lymph node cells (by i.d./i.d. model) and spleen cells (by i.d./i.p. model) was dose dependently increased. The secretion of Th1 cytokine IFN-γ in both tissue cells was significantly decreased by dibutyryl-cAMP (cAMP analog) and forskolin (adenylyl cyclase activator), as well as by the PDE4 inhibitor rolipram, indicating that the inhibitory effect of rolipram was mediated by an increase of cAMP in Th1 cells. In addition, the release of IL-17A in the spleen cells, but not the lymph node cells also was suppressed by these cAMP-elevationg agents. Moreover, like rolipram, the PDE3 inhibitor cilostazol also significantly attenuated the secretion of IFN-γ and IL-17A while having less extent. In a CII-primed model, anti-CD3/CD28 antibody-induced IFN-γ release in the mouse local lymph node and spleen cells was also significantly reduced by rolipram, but not by cilostazol. As for IL-17A, inhibition of PDE4 caused a significant decrease in IL-17A release in the spleen cells but not the lymph node cells. It was noted that in all CIA models tested IFN-γ and IL-17A release was almost completely inhibited when the two tissue cells were treated with rolipram in combination with cilostazol. Thus, the two inhibitors were used together to treat CIA mice and the results showed that the inhibition of both PDE4 and PDE3 significantly attenuated the arthritic severity. Moreover, using the CIA model in the PDE4B null mice revealed that ablation of PDE4B did not affect the development of arthritis, while administration of cilostazol to PDE4B null mice appeared to reduce the disease severity when compared with the control wild type mice. Taken together, these results indicate that inhibition of PDE4 can effectively reduce the CII-induced Th1 and Th17 responses, and inhibition of PDE3 exerts synergistic inhibitory effects in CIA mice. Our findings provide an experimental basis for developing PDE3/4 dual inhibitors for RA therapy. | en_US |