STRESS PROTEIN-INDUCED IMMUNOSUPPRESSION - INHIBITION OF CELLULAR IMMUNE EFFECTOR FUNCTIONS FOLLOWING OVEREXPRESSION OF HEME OXYGENASE (HSP-32)

This is the first report on suppression of immune effector functions f ollowing upregulation of heat shock protein 32 (HSP 32), known as haem oxygenase (HO-1). Here we evaluated the effect of cobalt-protoporphyr in (CoPP)-induced HO-1 expression on cell-mediated immune responses. A dministration of CoPP to CBA mice resulted in overexpression of HO-1 i n the spleen, liver and kidneys. In vitro measurements of T cell-media ted and NK-cell-mediated cytotoxicity in spleens from CoPP-treated ani mals demonstrated a severe suppression of their effector functions whi le administration of Zn-PP or vitamin B-12 had no effect. Furthermore, CoPP therapy decreased the lymphoproliferative alloresponse and diffe rentiation of cytotoxic T cells. Inhibition of proliferation appeared to be due to cell growth arrest with an increased number of cells stay ing in G(0)/G(1) phase. Despite the suppressed proliferative response, IL-2 production in the MLR was not inhibited. In contrast, CoPP decre ased the production of IL-10, IFN-gamma and TNF-alpha. In vivo, CoPP p rolonged the survival of heterotopic heart allografts in mice. The imm unosuppressive effects following CoPP-mediated upregulation of HO-1 we re similar to those observed after peptide-mediated upregulation of HO -1. The results indicate that overexpression of HO results in the inhi bition of several immune effector functions and thus provides an expla nation for stress-induced immunosuppression.