Colchicine-derived compound CT20126 promotes skin allograft survival by regulating the balance of Th1 and Th2 cytokine production

Abstract

Colchicine has been shown to regulate the expression of inflammatory gene, but this compound possesses much weaker anti-inflammatory activity. In this study, we synthesized a new colchicine derivative CT20126 and examined its immunomodulatory property. CT20126 was found to have immunosuppressive effects by inhibiting lymphocyte proliferation without cytotoxicity and effectively inhibit the transcriptional expression of the inflammatory genes, iNOS, TNF-α, and IL-1β, in macrophages stimulated by LPS. This effect was nearly comparable to that of cyclosporine A. This compound also significantly suppressed the production of nitric oxide and Th1-related pro-inflammatory cytokines, IL-1β, TNF-α, and IL-2, with minimal suppression of Th2-related anti-inflammatory cytokines IL-4 and IL-10 in the sponge matrix allograft model. Moreover, administration of CT20126 prolonged the survival of allograft skins from BALB/c mice (H-2 d ) to the dorsum of C57BL/6 (H-2 b ) mice. The in vivo immune suppressive effects of CT20126 were similar to that of cyclosporine A. These results indicate that this compound may have potential therapeutic value for transplantation rejection and other inflammatory diseases.

Icaritin inhibits T cell activation and prolongs skin allograft survival in mice

“…Acute allograft rejection is usually associated with the Th1 like cytokines, such as IL-2 and IFN-γ, although Th2 cytokines IL-4 can also be elevated in rejecting grafts. Treatment with immunosuppressants, such as tacrolimus (FK-506) and sirolimus (rapamycin), could decrease Th1 cytokines production and prolong allograft survival [26]. Cyclosporin A, as a calcineurin blocker, could inhibit IL-2 production of lymphocytes and serve as a useful therapy for transplantation rejection.…”

“…NF-AT was identified as a target for the immunosuppressants CsA and FK506 [26]. NF-AT is also a key transcription factor in CD4 + T cell activation, Th1/Th2 differentiation and T cell tolerance induction [27,28].…”

Syringaresinol causes vasorelaxation by elevating nitric oxide production through the phosphorylation and dimerization of endothelial nitric oxide synthase

“…The membranes were incubated with antibodies against target proteins for 2 h following pre-hybridization with bovine serum albumin. The signal intensities of immunoreactive bands were visualized by an enhanced chemiluminescence system, as described previously (Lee et al, 2007). …”

The colchicine derivative CT20126 shows a novel microtubule-modulating activity with apoptosis

“…Among them, the semisynthetic colchicine derivative CT20126 was found to act as an effective immunosuppressant. 15, 16 While examining the effects of CT20126, we noted that it triggered drastically different microtubule dynamics and apoptotic activity compared with colchicine. Cells treated with CT20126 resulted in an increase of sub-G1 population and caspase-3 activation, which suggests that CT20126 has potent apoptotic activity.…”