Stress protein-induced immunosuppression: inhibition of cellular immune effector functions following overexpression of haem oxygenase (HSP 32).
This is the first report on suppression of immune effector functions following upregulation of heat shock protein 32 (HSP 32), known as haem oxygenase (HO-1). Here we evaluated the effect of cobalt-protoporphyrin (CoPP)-induced HO-1 expression on cell-mediated immune responses. Administration of CoPP to CBA mice resulted in overexpression of HO-1 in the spleen, liver and kidneys. In vitro measurements of T cell-mediated and NK-cell-mediated cytotoxicity in spleens from CoPP-treated animals demonstrated a severe suppression of their effector functions while administration of Zn-PP or vitamin B12 had no effect. Furthermore, CoPP therapy decreased the lymphoproliferative alloresponse and differentiation of cytotoxic T cells. Inhibition of proliferation appeared to be due to cell growth arrest with an increased number of cells staying in G0/G1 phase. Despite the suppressed proliferative response, IL-2 production in the MLR was not inhibited. In contrast, CoPP decreased the production of IL-10, IFN-gamma and TNF-alpha. In vivo, CoPP prolonged the survival of heterotopic heart allografts in mice. The immunosuppressive effects following CoPP-mediated upregulation of HO-1 were similar to those observed after peptide-mediated upregulation of HO-1. The results indicate that overexpression of HO results in the inhibition of several immune effector functions and thus provides an explanation for stress-induced immunosuppression.
SangStat Medical Corporation, Menlo Park, California 94025, USA.
J
J
Woo
S
S
Iyer
M C
MC
Cornejo
N
N
Mori
L
L
Gao
I
I
Sipos
M
M
Maines
R
R
Buelow
D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D005434:Flow Cytometry; D006085:Graft Survival / Q000502:physiology; D016027:Heart Transplantation / Q000276:immunology; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis* / Q000276:immunology*; D007108:Immune Tolerance / Q000502:physiology*; D007111:Immunity, Cellular / Q000502:physiology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D011524:Protoporphyrins / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D016207:Cytokines; D011524:Protoporphyrins; C007095:cobaltiprotoporphyrin; D006419:Heme Oxygenase (Decyclizing)