Role of alveolar epithelial early growth response-1 (Egr-1) in CD8+ T cell-mediated lung injury.
Influenza infection of the distal airways results in severe lung injury, a considerable portion of which is immunopathologic and attributable to the host responses. We have used a mouse model to specifically investigate the role of antiviral CD8(+) T cells in this injury, and have found that the critical effector molecule is TNF-alpha expressed by the T cells upon antigen recognition. Interestingly, the immunopathology which ensues is characterized by significant accumulation of host inflammatory cells, recruited by chemokines expressed by the target alveolar epithelial cells. In this study we analyzed the mechanisms involved in the induction of epithelial chemokine expression triggered by antigen-specific CD8(+) T cell recognition, and demonstrate that the early growth response-1 (Egr-1) transcription factor is rapidly induced in epithelial cells, both in vitro and ex vivo, and that this is a critical regulator of a host of inflammatory chemokines. Genetic deficiency of Egr-1 significantly abrogates both the chemokine expression and the immunopathologic injury associated with T cell recognition, and it directly regulates transcriptional activity of a model CXC chemokine, MIP-2. We further demonstrate that Egr-1 induction is triggered by TNF-alpha-dependent ERK activation, and inhibition of this pathway ablates Egr-1 expression. These findings suggest that Egr-1 may represent an important target in mitigating the immunopathology of severe influenza infection.
Ramana
Chilakamarti V
CV
Department of Medicine, Dartmouth Medical School, Lebanon, NH 03756, USA. ramana.v.chilakamarti@dartmouth.edu
Cheng
Guang-Shing
GS
Kumar
Aseem
A
Kwon
Hyung-Joo
HJ
Enelow
Richard I
RI
D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D054426:Chemokine CXCL2 / Q000096:biosynthesis / Q000235:genetics; D018925:Chemokines / Q000276:immunology; D051766:Early Growth Response Protein 1 / Q000276:immunology*; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D020869:Gene Expression Profiling; D008171:Lung Diseases / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D054426:Chemokine CXCL2; D018925:Chemokines; D051766:Early Growth Response Protein 1; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D048049:Extracellular Signal-Regulated MAP Kinases