Article

The proinflammatory phenotype of PECAM-1-deficient mice results in atherogenic diet-induced steatohepatitis

Medical College of Wisconsin, Milwaukee, Wisconsin, United States
AJP Gastrointestinal and Liver Physiology (Impact Factor: 3.74). 01/2008; 293(6):G1205-14. DOI: 10.1152/ajpgi.00157.2007
Source: PubMed

ABSTRACT The severity of nonalcoholic steatohepatitis (NASH) is determined by environmental and genetic factors, the latter of which are incompletely characterized. Platelet endothelial cell adhesion molecule-1 (PECAM-1) is a 130-kDa transmembrane glycoprotein expressed on blood and vascular cells. In the present study, we provide data for the novel finding that genetic deficiency of PECAM-1 potentiates the development and progression of NASH. We found that the rate of development and severity of diet-induced NASH are markedly enhanced in PECAM-1-deficient [knockout (KO)] mice relative to wild-type (WT) mice, as measured by histological and biochemical evaluation. Livers from KO mice exhibited typical histological features of NASH, including macrovesicular fat accumulation, hepatocyte injury with infiltration of inflammatory cells, fibrosis, and heightened oxidative stress. Alanine aminotransferase, a marker for liver injury, was also significantly higher in KO compared with WT mice. Consistent with a role for PECAM-1 as a suppressor of proinflammatory cytokines, plasma levels of inflammatory cytokines, including TNF-alpha and monocyte chemoattractant protein-1 (MCP-1), were also significantly higher in KO compared with WT mice. These findings are the first to show that the PECAM-1-deficient mouse develops progressive nonalcoholic fatty liver disease (NAFLD), supporting a role for PECAM-1 as a negative regulator of NAFLD progression. Future examination of recently identified PECAM-1 allelic isoforms in humans as potential risk factors for developing NASH may be warranted.

0 Followers
 · 
87 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Although it is expressed by all leukocytes, including T-, B-lymphocytes and dendritic cells, the immunoglobulin-like receptor CD31 is generally regarded by immunologists as a marker of endothelial cell lineage that lacks an established functional role in adaptive immunity. This perception has recently been challenged by studies that reveal a key role for this molecule in the regulation of T-cell homeostasis, effector function and trafficking. The complexity of the biological functions of CD31 results from the integration of its adhesive and signaling functions in both the immune and vascular systems. Signaling by means of CD31 is induced by homophilic engagement during the interactions of immune cells and is mediated by phosphatase recruitment or activation through immunoreceptor tyrosine inhibitory motifs (ITIMs) that are located in its cytoplasmic tail. Loss of CD31 function is associated with excessive immunoreactivity and susceptibility to cytotoxic killing. Here, we discuss recent findings that have brought to light a non-redundant, complex role for this molecule in the regulation of T-cell-mediated immune responses, with large impact on our understanding of immunity in health and disease.
    Journal of Cell Science 06/2013; 126(11):2343-52. DOI:10.1242/jcs.124099 · 5.33 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To investigate the mechanism by which platelet endothelial cell adhesion molecule 1 (PECAM-1/CD31), an immunoglobulin (Ig)-superfamily cell adhesion and signaling receptor, regulates pro-inflammatory cytokine levels. The purpose of the present investigation was to test the hypothesis that PECAM-1 influences circulating cytokine levels by regulating the trafficking of activated, cytokine-producing leukocytes to sites of inflammation. PECAM-1+/+ and PECAM-1-/- mice were subjected to lipopolysaccharide (LPS)-induced endotoxemia, and systemic cytokine levels were measured by Bioplex multiplex cytokine assays. Flow cytometry was employed to enumerate leukocytes at inflammatory sites and to measure cytokine synthesis in leukocyte sub-populations. Enzyme-linked immunosorbent assay (ELISA) was used to measure cytokine levels in tissue samples and in supernatants of in vitro-stimulated leukocytes. We confirmed earlier reports that mice deficient in PECAM-1 had greater systemic levels of pro-inflammatory cytokines following intraperitoneal (IP) LPS administration. Interestingly, expression of PECAM-1, in mice, had negligible effects on the level of cytokine synthesis by leukocytes stimulated in vitro with LPS and in peritoneal macrophages isolated from LPS-injected mice. There was, however, excessive accumulation of macrophages and neutrophils in the lungs of PECAM-1-deficient, compared with wild-type, mice--an event that correlated with a prolonged increase in lung pro-inflammatory cytokine levels. Our results demonstrate that PECAM-1 normally functions to dampen systemic cytokine levels during LPS-induced endotoxemia by diminishing the accumulation of cytokine-producing leukocytes at sites of inflammation, rather than by modulating cytokine synthesis by leukocytes.
    Life sciences 11/2011; 90(5-6):177-84. DOI:10.1016/j.lfs.2011.11.002 · 2.30 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) is a cell adhesion and signaling receptor that is expressed on hematopoietic and endothelial cells. PECAM-1 is vital to the regulation of inflammatory responses, as it has been shown to serve a variety of pro-inflammatory and anti-inflammatory functions. Pro-inflammatory functions of PECAM-1 include the facilitation of leukocyte transendothelial migration and the transduction of mechanical signals in endothelial cells emanating from fluid shear stress. Anti-inflammatory functions include the dampening of leukocyte activation, suppression of pro-inflammatory cytokine production, and the maintenance of vascular barrier integrity. Although PECAM-1 has been well-characterized and studied, the mechanisms through which PECAM-1 regulates these seemingly opposing functions, and how they influence each other, are still not completely understood. The purpose of this review, therefore, is to provide an overview of the pro- and anti-inflammatory functions of PECAM-1 with special attention paid to mechanistic insights that have thus far been revealed in the literature in hopes of gaining a clearer picture of how these opposing functions might be integrated in a temporal and spatial manner on the whole organism level. A better understanding of how inflammatory responses are regulated should enable the development of new therapeutics that can be used in the treatment of acute and chronic inflammatory disorders.
    Life sciences 07/2010; 87(3-4):69-82. DOI:10.1016/j.lfs.2010.06.001 · 2.30 Impact Factor