Overexpression of CREM alpha in T Cells Aggravates Lipopolysaccharide-Induced Acute Lung Injury

Transcription factor cAMP response element modulator (CREM) a 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 CREM alpha is upregulated in LPS-induced ALI. During the early phase of ALI (day 1), T cell-specific CREM alpha overexpression enhances the numbers of T cells and expression of TNF-alpha in bronchoalveolar lavage fluid and deteriorates lung functions. On day 3 of ALI, CREM alpha transgenic mice present a stronger inflammatory response with higher levels of TNF-alpha, 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 CREM alpha 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 CREM alpha 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 CREM alpha and an increased susceptibility toward infectious complications, our finding is of potential clinical significance and may enable new therapeutic strategies.