Ischemic acute tubular necrosis induces an extensive local cytokine response. Evidence for induction of interferon-gamma, transforming growth factor-beta 1, granulocyte-macrophage colony-stimulating factor, interleukin-2, and interleukin-10.
We noted previously that ischemic acute tubular necrosis (ATN) induces local expression of MHC products in renal epithelium. The present investigations were conducted to establish the role of IFN-gamma in the regulation of MHC antigen expression in ATN and to explore the changes in cytokine and growth factor expression induced by ischemic renal injury. We produced unilateral ischemic ATN in mice by clamping the left renal pedicle. MHC class I and II steady state mRNA induction was assessed by northern blot analysis, and MHC product was quantified by the extent of binding of radiolabeled monoclonals to tissue homogenates. The steady state mRNA levels for IFN-gamma, IL-2, IL-10, and granulocyte-macrophage CSF were assessed by reverse transcriptase polymerase chain reaction and the levels for transforming growth factor-beta 1 and prepro-epidermal growth factor (ppEGF) were assessed by Northern blot analysis. In the injured kidneys, steady state mRNA levels for IFN-gamma, IL-2, IL-10, granulocyte-macrophage CSF, and transforming growth factor beta-1 were increased, whereas ppEGF mRNA was markedly decreased. The MHC expression was inhibited by treatment of mice with an anti-IFN-gamma mAb (R4-6A2). Murine EGF, administered in an attempt to accelerate recovery, did not reduce the cytokine and MHC changes. These data indicate that ischemic injury, and possibly other forms of injury, triggers a complex circuit of proinflammatory cytokines. This "injury response" could be relevant to clinical renal transplants, where ATN is associated with poor graft outcome.
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Division of Nephrology and Immunology, University of Alberta, Edmonton, Canada.
Urmson
J
J
Ramassar
V
V
Halloran
P F
PF
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001483:Base Sequence; D016207:Cytokines / Q000096:biosynthesis* / Q000187:drug effects; D018076:DNA, Complementary; D004195:Disease Models, Animal; D004815:Epidermal Growth Factor / Q000032:analysis / Q000494:pharmacology; D006649:Histocompatibility Antigens / Q000096:biosynthesis* / Q000187:drug effects; D007371:Interferon-gamma / Q000032:analysis / Q000276:immunology; D007511:Ischemia / Q000276:immunology; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D007683:Kidney Tubular Necrosis, Acute / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000032:analysis
D000911:Antibodies, Monoclonal; D016207:Cytokines; D018076:DNA, Complementary; D006649:Histocompatibility Antigens; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor; D007371:Interferon-gamma