Suppression of TNF-alpha expression, inhibition of Th1 activity, and amelioration of collagen-induced arthritis by rolipram.
Rolipram is a type IV phosphodiesterase inhibitor that suppresses inflammation and TNF-alpha production. As anti-TNF-alpha therapy is effective in rheumatoid arthritis, we investigated the effect of rolipram on collagen-induced arthritis (CIA), a murine model of rheumatoid arthritis. Rolipram was administered after the onset of clinical arthritis at doses of 0.5, 3, 5, or 10 mg/kg twice daily, with a dose-dependent therapeutic effect on clinical severity and joint erosion. Immunohistochemical analysis of joints of rolipram-treated mice revealed 67% reduction in TNF-alpha-expressing cells compared with control arthritic mice. In vitro studies using bone marrow-derived macrophages confirmed that rolipram directly suppressed TNF-alpha and IL-12 production following stimulation with IFN-gamma and LPS. The effect of rolipram on T cell activity was studied by measuring Th1/Th2 cytokine production by collagen-stimulated draining lymph node cells from arthritic mice treated in vivo with rolipram. Rolipram reduced IFN-gamma production and increased IL-10, indicating that rolipram down-regulated the ongoing Th1 response to type II collagen. Finally, the effect on CIA of combination therapy was studied using rolipram plus either anti-TNF-alpha or anti-CD4 mAbs. Rolipram plus anti-TNF-alpha was not therapeutically additive, whereas rolipram plus anti-CD4 mAb was clearly additive. This result indicates that the therapeutic effects of rolipram overlap with TNF-alpha blockade, but are complementary to anti-CD4 treatment. It is therefore proposed that a major mechanism of action of rolipram in CIA is suppression of TNF-alpha activity. These findings suggest that type IV phosphodiesterase inhibitors may be effective in pathologic conditions, such as RA, with overexpression of TNF-alpha.
Ross
S E
SE
Kennedy Institute of Rheumatology, London, United Kingdom.
Williams
R O
RO
Mason
L J
LJ
Mauri
C
C
Marinova-Mutafchieva
L
L
Malfait
A M
AM
Maini
R N
RN
Feldmann
M
M
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001168:Arthritis / Q000188:drug therapy / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology; D002417:Cattle; D003094:Collagen / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004359:Drug Therapy, Combination; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D011760:Pyrrolidinones / Q000494:pharmacology* / Q000627:therapeutic use; D020889:Rolipram; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000276:immunology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D016207:Cytokines; D007166:Immunosuppressive Agents; D011760:Pyrrolidinones; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D003094:Collagen; D020889:Rolipram