Effect of redox modulation on xenogeneic target cells: The combination of nitric oxide and thiol deprivation protects procine endothelial cells from lysis by IL-2-Activated human NK cells

Evidence suggests that NK cells contribute to the pathogenesis of delayed r ejection of vascularized xenografts, and NK cells have been suggested to pa rticipate in hyperacute xenograft rejection. Endothelial cells have been sh own to be the primary target of the recipient's immune responses that media te both hyperacute and delayed xenograft rejection. Under conditions of oxi dative stress induced by thiol deprivation, but not under normal conditions , pretreatment of porcine aortic endothelial cells (PAECs) with the NO dono r, S-nitroso-N-acetyl-penicillamine, dramatically inhibited killing of PAEC target cells by IL-2-activated human NK cells. This same combined treatmen t reduced both surface expression and mRNA levels of E-selectin, Moreover, anti-E-selectin mAb, but not Ab to VCAM-1, protected PAEC from lysis by hum an IL-2-activated NK cells in a dose-dependent manner. These findings Sugge st that expression of porcine E-selectin is important for the cytotoxicity of PAEC mediated by activated human NK cells and mag be involved in the red ox-mediated modulation of that cytotoxicity. It is known that NF-kappaB act ivation is required for transcription of E-selectin, and the current data s how that the suppression of E-selectin expression by S-nitroso-N-acetyl-pen icillamine pretreatment and thiol deprivation was associated with reduced N F-kappaB DNA-binding activity in PAEC. These data suggest that the regulati on of porcine E-selectin may be important for modulating delayed xenograft rejection and that manipulation of cellular redox systems may provide a mea ns to protect xenogeneic endothelial cells from NK cell-mediated cytotoxici ty.