Endothelial Cells Require STAT3 for Protection against Endotoxin-induced Inf lammation

Abstract

Endothelial cells (ECs) are believed to be an important component in the protection from lipopolysaccharide (LPS)-induced endotoxic shock. However, the cellular and molecular mechanism is not well defined. Here, we report that signal transducer and activator of transcription (STAT) 3 is an essential regulator of the antiinflammatory function of ECs in systemic immunity. Because STAT3 deficiency results in early embryonic lethality, we have generated mice with a conditional STAT3 deletion in endothelium (STAT3E−/−). STAT3E−/− mice are healthy and fertile, and isolated ECs initiate normal tube formation in vitro. Conditional endothelial but not organ-specific (i.e., hepatocyte or cardiomyocyte) STAT3 knockout mice show an increased susceptibility to lethality after LPS challenge. The LPS response in STAT3E−/− mice shows exaggerated inflammation and leukocyte infiltration in multiple organs combined with elevated activity of serum alanine aminotransferase and aspartate aminotransferase, indicating organ damage. Concomitantly, proinflammatory cytokines are produced at an exaggerated level and for a prolonged period. This defect cannot be explained by lack of antiinflammatory cytokines, such as interleukin 10 and transforming growth factor β. Instead, we have shown that a soluble activity derived from endothelia and dependent on STAT3 is critical for suppression of interferon γ. These data define STAT3 signaling within endothelia as a critical antiinflammatory mediator and provide new insight to the protective function of ECs in inflammation.

Lack of gp130 expression results in more bacterial infection and higher mortality during chronic cholestasis in mice

“…11 Therefore, our experiments can not differentiate between the effect of gp130-dependent pathways triggered in hepatocytes, nonparenchymal cells or immune activated cells that all may contribute to restrict bacterial growth and eliminate them from the body. Recent experiments published by Kano et al 21 suggest that endothelial cells could also be involved in this regulation. They show that lack of Stat3 expression results in higher interferon-␥ (IFN-␥) and IL-6 expression after lipopolysaccharide (LPS) injection.…”

Stat3 regulates genes common to both wound healing and cancer

“…This finding is consistent with previous studies showing that cells exposed to IL-6 require Stat3 to downregulate Stat1 activity and prevent an IFNg-like response (CostaPereira et al, 2002). Selective loss of Stat3 in endothelial cells results in expanded inflammatory response and tissue damage in response to a systemic inflammatory response (Kano et al, 2003). These conditional Stat3-null animals demonstrated increased levels and prolonged periods of proinflammatory cytokine production.…”

Critical Role for STAT3 in IL-17A-Mediated CCL11 Expression in Human Airway Smooth Muscle Cells

“…Within the nucleus, STAT3 binds specific DNA motifs and activates the transcription of distinct groups of genes (11). Cell-specific disruption of STAT3 in endothelial or myeloid cells suggests mainly an anti-inflammatory role of STAT3 in innate immune response (41). Additional evidence for a central role of STAT3 in regulating the anti-inflammatory response comes from skin and liver pathological models (41,42).…”