Intragraft TNF receptor signaling contributes to activation of innate and adaptive immunity in a renal allograft model

Mary Hummel, Sunil M. Kurian, Simon Lin, Aleksey Borodyanskiy, Zheng Zhang, Zhigao Li, Soo Jung Kim, Daniel R. Salomon, Michael Abecassis

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


BACKGROUND.: Increased levels of tumor necrosis factor (TNF) are a risk factor for allograft rejection. In vitro studies have shown that binding of TNF to its receptor activates signaling cascades that induce expression of many genes involved in inflammation. The role of intragraft TNF receptor (TNFR) signaling in activation of gene expression in allografts has not been studied. METHODS.: Gene expression profiling and quantitative real-time polymerase chain reaction analysis were used to investigate the role of TNFR signaling in the early intragraft activation of cellular gene expression in renal allografts at 2 days posttransplant. RESULTS.: The TNFRs play a critical role in activating intragraft expression of transcription factors controlling innate and adaptive immunity and stress responses (interferon regulatory factor {lsqb;IRF{rsqb;1, IRF 8, Isgf3g, and ATF3) of cytokines and receptors mediating inflammation (TNF, interleukin [IL]-6, interferon-γ, oncostatin M receptor {lsqb;OMCR{rsqb;, toll-like receptor {lsqb;TLR{rsqb;2, and IL-2Rγ), of chemokines and adhesion molecules that recruit inflammatory cells (Cxcl9, Cxcl11, E-selectin, and intracellular adhesion molecule {lsqb;ICAM{rsqb;-1), of genes involved in costimulation of T cells and processing and presentation of antigens (H2-DMb, Psmb8, and CD40), and genes that mediate the response to interferons. In addition to its proinflammatory role, TNFR signaling induces expression of SOCS3, a negative regulator of IL-6 and OSMR signaling and Nfkbie, and a negative regulator of TNFR signal transduction. CONCLUSIONS.: These studies illustrate the pleiotropic effect of TNF in both activation and down-modulation of the immune response and the complex interactions between the TNFRs and other cytokine signaling pathways in the early allograft response.

Original languageEnglish (US)
Pages (from-to)178-188
Number of pages11
Issue number2
StatePublished - Jan 27 2009
Externally publishedYes


  • Allograft
  • Gene expression profiling
  • TNF

ASJC Scopus subject areas

  • Transplantation


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