Interleukin-12p70 prolongs allograft survival by induction of interferon gamma and nitric oxide production

Nirupama Darshan Verma, Rochelle Boyd, Catherine M Robinson, Karren Michelle Plain, Giang T Tran, Bruce M Hall

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

BACKGROUND: Interleukin (IL)-12p70, a heterodimeric cytokine has been considered central to induction of Th1 responses with the assistance of IL-18 and IL-27. It was predicted IL-12p70 treatment would promote allograft rejection. In these studies, IL-12p70 delayed rejection.

METHODS: We compared Piebald Virol Glaxo (PVG) neonatal heart graft survival in fully allogeneic Dark Agoutti (DA) rats treated with IL-12p70 alone or in combination with other cytokines. The mechanism by which IL-12p70 induced delayed rejection was examined by reverse transcription polymerase chain reaction of cytokine mRNA and studying the role of interferon (IFN)-gamma and inducible nitric oxide synthase (iNOS) that were induced by IL-12.

RESULTS: IL-12p70 treatment significantly delayed PVG neonatal heart graft rejection compared to normal rejection control and other control groups treated with supernatant from Chinese hamster ovary (CHO)-K1 cells transfected with IL-12p35, IL-12p40, or no cytokine gene. IL-12p70 had no effect on alloantibody response. IFN-gamma and iNOS mRNA expression was increased in heart graft and regional lymph node compared to normal rejection and other treatment groups, consistent with Th1 response induction. IL-12p35 mRNA expression decreased in IL-12p70 treated rats but there was no difference in IL-12p40, Th2, or Tr1 cytokine mRNA expression. Coadministration of an iNOS inhibitor, L-NIL, or a monoclonal antibody (mAb) that blocks IFN-gamma, inhibited IL-12p70's ability to prolong allograft survival; as did co-treatment with IL-4 but not IL-13.

CONCLUSIONS: IL-12p70 treatment may inhibit rejection by hyperinduction of Th1 responses, especially production of IFN-gamma and nitric oxide. These effects may be by enhancing regulatory T-cell responses or by the activation of iNOS in macrophages to produce excessive nitric oxide that in turn inhibits alloimmune responses.

Original languageEnglish
Pages (from-to)1324-33
Number of pages10
JournalTransplantation
Volume82
Issue number10
DOIs
Publication statusPublished - 27 Nov 2006
Externally publishedYes

Keywords

  • Animals
  • Animals, Newborn
  • Crosses, Genetic
  • Cytokines
  • Graft Survival
  • Heart Transplantation
  • Interferon-gamma
  • Interleukin-12
  • Interleukin-13
  • Interleukin-4
  • Isoantibodies
  • Models, Animal
  • Nitric Oxide
  • RNA, Messenger
  • Rats
  • Rats, Inbred Strains
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transplantation, Homologous
  • Journal Article
  • Research Support, Non-U.S. Gov't

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