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The IkB family member Bcl‐3 regulates lung graft inflammation and injury
Author(s) -
Gelman Andrew E,
Kreisel Daniel,
Sugimoto Seiichiro,
Tietjens Jeremy
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.47.5
Subject(s) - inflammation , monocyte , lung , macrophage , immunology , medicine , lung transplantation , cancer research , tumor necrosis factor alpha , transplantation , ccl2 , biology , chemokine , biochemistry , in vitro
The IκB family member Bcl‐3 was recently shown to enhance the stability of p50 homodimers which in turn can inhibit the expression of NF‐κB dependent genes. However, the role of Bcl‐3 in solid organ injury is unknown. We asked if Bcl‐3 regulates ischemia‐reperfusion (I/R) injury in a mouse model of syngeneic orthotopic lung graft transplantation. B6→B6 and B6→Bcl‐3 − /− transplants were compared for lung graft inflammation and function following cold ischemia and 24 hrs of reperfusion. Loss of Bcl‐3 expression resulted in exacerbated inflammatory mediator synthesis, pulmonary edema and poor graft function. However, I/R injury could be significantly averted in Bcl‐3 − /− recipients by using an NF‐κB inhibitor indicating that Bcl‐3 controls graft inflammation through targeting NF‐κB activity. Also, we found 3‐fold more TNFα‐producing macrophages in the airways of Bcl‐3 − /− recipients in comparison to B6 recipients. BrdU injection of Bcl‐3 − /− recipients revealed that the elevated macrophage sequestration was not a result of altered monocyte chemotaxis but due to significantly higher numbers of dividing graft‐infiltrating monocytes and macrophages. Analysis of M‐CSF treated‐BrdU pulsed monocyte cultures also showed comparatively greater BrdU uptake and macrophage production from Bcl‐3 − /− monocytes. Our data reveal that Bcl‐3 is a critical regulator of lung graft injury and inflammatory monocyte differentiation.