title: Overexpression of CREMα in T cells aggravates lipopolysaccharide-induced acute lung injury.
abstract: Transcription factor cAMP response element modulator (CREM)α contributes to various cellular and molecular abnormalities in T cells, including increased IL-17 and decreased IL-2 expression. For development of acute lung injury (ALI), the invasion and regulation of immune cells are highly important, but the role of T cells remains unclear. In this study, we show that CREMα is upregulated in LPS-induced ALI. During the early phase of ALI (day 1), T cell-specific CREMα overexpression enhances the numbers of T cells and expression of TNF-α in bronchoalveolar lavage fluid and deteriorates lung functions. On day 3 of ALI, CREMα transgenic mice present a stronger inflammatory response with higher levels of TNF-α, IL-6, and IL-17 correlating with increased numbers of T cells and neutrophils in bronchoalveolar lavage fluid, whereas expression of Foxp3 and IL-2 and numbers of regulatory T cells are decreased. These changes result in restricted lung function in CREMα transgenic mice. Finally, an adoptive transfer of CREM(-/-) CD4(+) T cells, but not of wild-type T cells into RAG-1(-/-) mice results in ameliorated disease levels. Thus, levels of CREM in T cells determine the outcome of ALI, and CREMα transgenic animals represent a model in which proinflammatory T cells aggravate ALI in different phases of the disease. Given the fact that patients with autoimmune diseases like systemic lupus erythematosus show higher levels of CREMα and an increased susceptibility toward infectious complications, our finding is of potential clinical significance and may enable new therapeutic strategies.
authors.affiliation: Department of Pediatrics, Medical Faculty, Rheinisch-Westfaelische Technische Hochschule Aachen University, 52074 Aachen, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Verjans
authors.forename: Kim
authors.initials: K
authors.lastname: Ohl
authors.forename: Yin
authors.initials: Y
authors.lastname: Yu
authors.forename: Ralph
authors.initials: R
authors.lastname: Lippe
authors.forename: Angela
authors.initials: A
authors.lastname: Schippers
authors.forename: Anastasia
authors.initials: A
authors.lastname: Wiener
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
authors.forename: Norbert
authors.initials: N
authors.lastname: Wagner
authors.forename: Stefan
authors.initials: S
authors.lastname: Uhlig
authors.forename: Klaus
authors.initials: K
authors.lastname: Tenbrock
authors.forename: Christian
authors.initials: C
authors.lastname: Martin
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000276:immunology*; D019264:Adoptive Transfer; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D051786:Cyclic AMP Response Element Modulator / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018398:Homeodomain Proteins; D020381:Interleukin-17; D007376:Interleukin-2; D015850:Interleukin-6; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C064658:RAG-1 protein; D051786:Cyclic AMP Response Element Modulator