Intragraft TNF receptor signaling contributes to activation of innate and adaptive immunity in a renal allograft model.
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 [IRF]1, IRF 8, Isgf3g, and ATF3) of cytokines and receptors mediating inflammation (TNF, interleukin [IL]-6, interferon-gamma, oncostatin M receptor [OMCR], toll-like receptor [TLR]2, and IL-2Rgamma), of chemokines and adhesion molecules that recruit inflammatory cells (Cxcl9, Cxcl11, E-selectin, and intracellular adhesion molecule [ICAM]-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.
Hummel
Mary
M
Transplant Division, Department of Surgery, Northwestern University, Chicago, IL, USA.
Kurian
Sunil M
SM
Lin
Simon
S
Borodyanskiy
Aleksey
A
Zhang
Zheng
Z
Li
Zhigao
Z
Kim
Soo Jung
SJ
Salomon
Daniel R
DR
Abecassis
Michael
M
D000818:Animals; D016207:Cytokines / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D007113:Immunity, Innate / Q000235:genetics; D007249:Inflammation / Q000235:genetics / Q000276:immunology*; D007668:Kidney / Q000276:immunology* / Q000601:surgery*; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000276:immunology*; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D016207:Cytokines; D018124:Receptors, Tumor Necrosis Factor; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha