| dc.description.abstract | Rheumatoid arthritis (RA) is a complicated, chronic autoimmune disorder that affects 1-2% population worldwide. It primarily attacks cartilage and bone of joints. The etiology of the disease still remains to be defined. Accumulating evidence indicates that elevation of intracellular cAMP concentration can suppress a vast spectrum of inflammatory responses in most immune cells and, thereby ameliorate chronic inflammatory diseases, such as asthma, COPD, and atopic dermatitis. Type 4 phosphodiesterases (PDE4s) are the major cAMP-hydrolyzing enzymes in various inflammatory cells. Inhibition of PDE4, thus increasing intracellular cAMP, has been considered an attractive strategy for developing anti-inflammatory drugs. Using collagen-induced arthritis (CIA) models, previous studies show potential benefits of PDE4 inhibitors in RA, while the mechanism of the effect remains unclear. Moreover, the Th1 and Th17 cytokines IFN- and IL-17A, respectively, are known important in the pathogenesis of RA. Therefore, in this study we employed CIA models to access whether PDE4 or cAMP signaling is involved in regulation of Th1 and Th17 responses in RA. By immunization of C57BL/6 and DBA/1 mice with chick collagen II (CII), we found that the disease incidence for the two mouse strains were 45% and 91%, respectively, and the arthritic symptoms developed during 21-42 and 27-33 days, respectively, after collagen immunization. In addition, the C57BL/6 mice, considered genetically resistant to CIA in early studies, also developed severe arthritic conditions. Immunization of DBA/1 mice with CII by different protocols (i.e. the id./id. and id./ip. models) indicated that both models induced the activation of CII-specific Th1 and Th17 cells in the spleen and draining (inguinal) lymph nodes of these mice. In vitro stimulation with CII and/or -CD3 antibody revealed a significant increase in IFN-and IL-17A release in T cells of the two lymphoid tissues from the two models, and these responses were significantly inhibited by the PDE4 inhibitor rolipram except for the release of IL-17A in the inguinal lymph node cells. The non-selective PDE inhibitor IBMX also attenuated IFN- and IL-17A release in these T cells to an extent similar to that of rolipram, indicating PDE4 is the major PDE isozymes in regulation of the Th1 and Th17 responses. Studies with the cAMP-elevating agents dbcAMP and forskolin and with PKA and Epac activators and inhibitors further suggested that the inhibitory effect of rolipram was mediated by activation of the cAMP/PKA axis. The PDE3 inhibitor cilostazol and PDE7 inhibitor BRL 50481 mostly had no effect on the Th1 and Th17 responses, whereas cilostazol showed synergistic effect to the rolipram inhibition. In conclusion, these findings indicate that PDE4 selective inhibitors can efficaciously alleviate inflammation in RA, yet PDE3 and PDE4 dual inhibitors may be more beneficial to RA patients. | en_US |