Abstract
The immunosuppressant Protosappanin A (PrA), isolated from the medicinal herb, promotes cardiac allograft survival, diminishes inflammatory cell infiltration, and inhibits interferon γ-induced protein 10 kDa (IP-10) mRNA expression in rats cardiac grafts. Binding of the chemokine IP-10 to its cognate receptor, CXCR3, plays crucial roles in allograft immunity, especially by mediating the recruitment of effector T cells to allografted tissues. In this study, we attempted to determine whether PrA-mediated inhibition of IP-10 contributes to the effect of reduced T cell infiltration into cardiac allograft within a rat model. Administration of PrA (25 mg/kg daily) via oral gavage following heart transplantation significantly reduced the increase of IP-10 mRNA level in allograft and prevented IP-10 secretion by peripheral blood mononuclear cells (PBMC) isolated from recipient rats seven days posttransplantation. Furthermore, in vitro experiments demonstrated that PrA addition to control PBMC prevented IP-10 secretion. Chemotactic migration assays were utilized to evaluate recipient T cell migration towards PBMC supernatant. PrA administration impaired PBMC supernatant-induced T cell migration. Additional in vitro experiments revealed that PrA slightly reduced naïve T cell migration towards chemokines. The presence of IP-10 in PBMC supernatant prevented PrA from reducing T cell migration in PrA-treated recipients. Neither CXCR3 chemokine ligand Mig nor non-CXCR3 chemokine ligand SDF-1 had any effect on T cell migration in PrA-treated recipients. The addition of anti-CXCR3 antibody restored PrA-mediated inhibition of T cell migration. Immunofluorescence microscopy showed that IP-10 was expressed mainly in CD68 positive infiltrating monocytes. Furthermore, PrA consistently reduced CXCR3+T cell infiltration into cardiac allografts. The reduced intensity of CXCR3 staining in PrA-treated allografts contributed to the previously depressed naïve T cell migrating activity induced by PrA. Collectively, these data indicate that PrA inhibition of IP-10 activity reduced recipient T cell migration and infiltration of cardiac allografts, thus partially explaining the immunosuppressive effect of PrA.
Highlights
The Chinese herb Caesalpinia sappan L. shows biological activities and provides therapeutic potential for some diseases, ranging from autoimmune disease to cancer [1,2,3,4,5]
In this study we evaluated whether protosappanin A (PrA) inhibition of induced protein 10 kDa (IP-10) expression results in reduced T cell infiltration into heart allografts
We have demonstrated the immunosuppressive effect of PrA on cardiac allografts
Summary
The Chinese herb Caesalpinia sappan L. shows biological activities and provides therapeutic potential for some diseases, ranging from autoimmune disease to cancer [1,2,3,4,5]. Recent research efforts have aimed to isolate and identify the bioactive components of this Chinese herb in order to generate more robust drug therapies and gain a better understanding of the molecular mechanisms underlying its therapeutic effects. An ethanol isolated extract from Caesalpinia sappan L., protosappanin A (PrA), was found to have remarkable anti-rejection activity [6]. Molecular studies have suggested that the mechanisms by which PrA protects cardiac allografts from acute rejection may involve the suppression of NF-kB activation and the reduced expression of interferon c-induced protein 10 kDa (IP-10) [7]. The precise underlying immunosuppressive mechanism of PrA remains to be fully elucidated
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