The Effect of Asarinin on Toll-Like Pathway in Rats After Cardiac Allograft Implantation

• This manuscript is part of our research supported by national nature fund, we studied systematically the effect of Asarinin on Toll-like 4 recetpor pathway in vitro, it is proved that Asarinin can inhibited expression TLR4 patheway in vitro, in this manuscript we study the expressison of TLR4 and related chemotactic factor-CXCR3 through SD rats allografts.
• Recently, a family of receptors—the toll like receptors r(TLR)— has been described that provides a critical link between immune stimulants produced by microorganisms and the initiation of host defense. Activation of these receptors results in the release of antimicrobial peptides, inflammatory cytokines, and costimulatory molecules which initiate adaptive immunity.
• The response of Toll-like receptor 4 (TLR4) to lipopolysaccharide (LPS) is thought vital for resisting foreign antigen, Since aberrant TLR4 signaling may initiate inflammatory conditions such as the sepsis syndrome, LPS potently induces dendritic cell maturation and the production of prionflammatory cytokines, such as IL-12, by activation of Toll-like receptor 4 (TLR4).
• IL-12 is important for the generation and maintenance of Th1 responses and may also inhibit Th2 cell generation from naive CD4 T cell precursors. It has, therefore, been inferred that TLR4 signaling would have similar effects via the induction of IL-12 secretion. Interleukin-12(IL-12) is crucial for the development of T helper cell responses in acute graft rejection, when immune reaction is inhibited, the expression of IL-12 will decreased simultaneously.
• Dentritic cells and macrophagocytes can activate chemokine receptor 3 (CXCR3), activation of TLR4 will secret CXC, which combied with CXCR3 and release Chemotactic factor, then reject reaction will turned into specific immune reaction. These findings suggest that local control of TLR4 may be a new therapeutic approach to suppression of anti-rejection.

ObjectiveThe objective of this study was to study the mechanism of the anti-rejection effect of Asarinin in rats that underwent cardiac allograft implantation.MethodsHearts from Wistar rats were transplanted into the abdominal cavity of Sprague Dawley rats (SD rats) 64 SD rats received either cyclosporin A (CsA), Asarinin, or demi-dose of cyclosporine A and Asarinin through oral administration. On the seventh day post-transplantation, the expression of Toll-like receptor 4 (TLR4), chemokine (C-X-C motif) receptor 3 (CXCR3) in myocardium, and the level of interleukin (IL)-12 in the peripheral blood were analyzed 7 days after transplantation.ResultsThe survival time in 3 groups (CsA group, Asarinin group, and semi-dose CsA group) prolonged (P < .01), the microscope myocardial histopathology in 3 groups (CsA group, Asarinin group and semi-dose CsA group) relieved, the expression of TLR4 and CXCR3 in 3 groups was significantly decreased (P < .01) when compared with the control group. The level of IL-12 decreased remarkably (P < .05) in the 3 groups when compared with the control group.ConclusionsThe combined data suggested that Asarinin decreased peripheral blood concentration of IL-12 and inhibited the expression of TLR4 and CXCR3, which means Asarinin may have a role on TLR4 pathway and produced prolongation of allograft heart survival.