Premium
Molecular profiling of the role of the NF‐κB family of transcription factors during alloimmunity
Author(s) -
Finn Patricia W.,
He Hongzhen,
Ma Chunyan,
Mueller Thomas,
Stone James R.,
Liou HsiouChi,
Boothby Mark R.,
Perkins David L.
Publication year - 2002
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.72.5.1054
Subject(s) - alloimmunity , biology , effector , immunology , immune system , transcription factor , transgene , p50 , chemokine , transplantation , nf κb , genetically modified mouse , signal transduction , cancer research , microbiology and biotechnology , gene , genetics , medicine
Allograft rejection involves a complex network of multiple immune regulators and effector mechanisms. In the current study, we focused on the role of nuclear factor (NF)‐κB/Rel. Previous studies had established that deficiency of the p50 NF‐κB family member prolonged allograft survival only modestly. However, because of its crucial role in signal transduction in inflammatory and immune responses, we hypothesized that other NF‐κB/Rel family members may produce more profound effects on alloimmunity. Therefore, in addition to p50, we analyzed the role of c‐Rel, which is expressed predominantly in lymphocytes. Also, to investigate NF‐κB activation in T cells, we examined transgenic mice that express a transdominant inhibitor of NF‐κB [IκB(ΔN)] regulated by a T cell‐restricted promoter. Allograft survival was prolonged indefinitely in the c‐Rel‐deficient and IκB(ΔN)‐transgenic recipients. To determine the molecular basis of NF‐κB modulation of rejection, we analyzed a panel of 58 parameters including effector molecules, chemokines, cytokines, receptors, and cellular markers using hierarchical clustering algorithms and self‐organizing maps in p50 −/− , c‐Rel −/− , and IκB(ΔN)‐transgenic, experimental groups plus allogeneic‐, syngeneic‐, and lymphocyte‐deficient (alymphoid) control groups. Surprisingly, profiles of gene expression in the c‐Rel recipients (which have indefinite graft survival) were similar to the p50 −/− and allogeneic recipients (which rapidly reject grafts). As expected, gene expression in the IκB(ΔN) recipients (which also have indefinite graft survival) was similar to profiles of nonrejecting syngeneic and alymphoid recipients. Importantly, self‐organizing maps identified a small subset of genes including several chemokine receptors and cytokines with expression profiles that correlate with graft survival. Thus, our results demonstrate a crucial role for NF‐κB in acute allograft rejection, identify different molecular mechanisms of rejection by distinct NF‐κB family members, and identify a small subset of inducible genes whose inhibition is linked to graft acceptance.