Am-80 is a newly snythesized retinoid with the structure of one aromatic amide among retinobenzoic acids. It exhibits specific biological activities of retinoic acid such as the activation of cellular differentiation and proliferation. We investigated the effect of Am-80 on collagen-induced arthritis (CIA) in mice and the immunopharmacological action on the production of several cytokines in the in vitro and in vivo models. Am-80, at doses of 0.3, 1 and 3 mg/kg, significantly inhibited the severity and development of the arthritis index, progression of foot pad swelling, bone damage and histopathological alterations. Am-80 also inhibited the production of anti-type II collagen (CII) IgG antibody, but did not affect the delayed-type hypersensitivity (DTH) response in arthritic mice. To determine the inhibitory mechanism of Am-80, we studied the effect of Am-80 on the production of cytokines. Am-80 did not affect the production of IFN-γ by Th1 cells (1E10.H2 cells) and IL-4 by Th2 cells (D10.G4.1 cells), respectively. Am-80 selectively inhibited bacterial lipopolysaccharide (LPS)-induced IL-6, but not TNF-α and IL-1β, production in mice. Moreover Am-80 inhibited IL-1β induced IL-6 production and IL-6 mRNA expression in human osteoblast-like cells (MG-63). The inhibition of IL-6 production by Am-80 was due to downregulation of the pretranscription or the transcription of IL-6 in MG 63 cells. These findings suggest that the inhibitory effect of Am-80 on CIA is partially by modulating the production of the proinflammatory cytokine, IL-6.

This study was conducted to investigate the mechanism of interleukin-1beta (IL-1beta)-induced IL-6 production in human osteoblasts (MG-63 cells). Stimulation with IL-1beta resulted in the production of IL-6 and prostaglandin E(2) (PGE(2)). IL-6 production gradually increased and peaked 96 h after stimulation. IL-6 mRNA was detected between 4 and 72 h after IL-1beta stimulation. The patterns of PGE(2) production and the expression of cyclooxygenase-2 (COX-2) mRNA were biphasic after stimulation. Actinomycin D, cycloheximide, indomethacin, and NS-398 (COX-2 inhibitor) suppressed the production of IL-6 and PGE(2). Anti-PGE(2) antibody markedly reduced the production of IL-6. In addition, stimulation with 17-phenyl-PGE(2), a PGE receptor-1 (EP-1 receptor) agonist, led to the expression of IL-6 mRNA after pretreatment with IL-1beta. These findings indicate that IL-1beta-induced IL-6 production in MG-63 cells involves the following sequence of steps: IL-1beta-induced COX-2 activation, PGE(2) production, and EP-1 receptor signaling prior to IL-6 production.

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TRK-530 is a newly synthesized diphosphonate derivative. We investigated the effect of TRK-530 on type II collagen-induced arthritis (CIA) in mice in comparison to that of prednisolone and indomethacin. TRK-530 at a dose of 25 mg/kg showed a tendency to inhibit CIA. TRK-530 at a dose of 50 mg/kg inhibited the development of the CIA in terms of the progression of footpad swelling, bone damage and histopathological changes. TRK-530 at a dose of 50 mg/kg also significantly inhibited the delayed type hypersensitivity (DTH) response to type II collagen, but not the production of anti-type II collagen IgG antibody in arthritic mice. To investigate the inhibitory mechanism of TRK-530, the type of effect of TRK-530 on the production of IL-1 beta in vitro was studied. TRK-530 at a concentration of 10(-4) M inhibited LPS-induced IL-1 beta production from J774.1 cells. In conclusion, TRK-530 inhibited CIA in mice. The inhibition of the DTH reaction to type II collagen and the inhibition of IL-1 beta production may partly participate the anti-rheumatoid action of TRK-530.