Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) - Volume 16, Issue 3, 2016

Stromal vascular fraction of the adipose tissue is recognized as reservoir of the cell populations with stem and progenitor properties. Besides the roles of adipose tissue stem and progenitor cells (ASPCs) in adipose tissue development and homeostasis, particularly interest is given to their functions in adipose tissue expansion and obesity. Obesity-driven low-grade chronic inflammation, reduction of oxygen level in adipose tissue and engagement of bone marrow, support recruitment of various progenitor cells in adipose tissue. Activation of bone marrow-adipose tissue axis regulates hematopoiesis and infiltration of immune cells in adipose tissue. Obesity-associated factors can provoke alteration of ASPC multipotent differentiation and immunosuppressive potential. Determination of underpinning mechanisms in altered (obese) ASPC phenotype may contribute to development of novel approaches for treatment of metabolic disorders and advancement the safety and efficiency of adipose tissue grafting.

Background: Angiotensin and its precursor’s peptides contribute to multiple biological functions and regulate several important mechanisms like hormone production, fluid balance, growth, and apoptosis throughout the body. The function of Ang-II is generally mediated through AT1R and AT2R which monitor various crucial pathways. Angiotensin receptors are largely expressed in various organs such as kidney, heart, adrenal cortex, smooth muscle, brain, pancreas, endothelial cells as well as liver. Ang-II is now considered responsible for end organ dysfunction particularly mediated through oxidative stress. Methods: We performed detailed searches in PubMed and Google scholar and compiled the literature on angiotensin mediated liver dysfunction using the key words alone or in combination such as angiotensin, liver dysfunction, oxidative stress etc. Results: The texts and tables presented herein consolidate the current data and ongoing research regarding angiotensin II and hepatic dysfunction. A cross talk between the AT receptors, NADP(H) oxidase and mitochondrial ROS generation have been found in literatures and are now well established. These particular phenomena attributed the hepatocyte dysfunction in liver which in turn leads to hepatic inflammation and fibrosis. Hemeoxygenase, an iron metabolizing protein is also degraded by overproduction of Ang-II and AT1R that finally triggers severe hepatic injuries. Ang-II activity was also found to be increased in non-alcoholic fatty liver diseases and viral hepatitis. Conclusion: This review work identifies the possible interaction and mechanisms of liver dysfunction mediated through Ang-II and AT receptor functions.

Background: Vasoactive intestinal peptide (VIP) is a 3.3 kDa pleiotropic protein with a broad expression profile that displays immune modulating activities. VIP binds two G protein-coupled receptors called Vasoactive Intestinal Pepide/Pituitary Adenylate Cyclase activating polypeptide receptor (VPAC) 1 and 2 that elicit multiple downstream signaling molecules, including adenylate cyclase. VIP differentially regulates over 300 genes in resting and activated murine CD4 T cells, and is chemotactic to resting and Th2 effector T cells. Objective: This study is focused on delineating which human VIP receptor, called VPAC1 and VPAC2, controls T cell biology pertaining to gene expression, signaling and chemotaxis. Method: To this end, we utilized human T cell lines known to exclusively express VPAC1, (HuT-78) or VPAC2 (Molt-4) in an attempt to identify VIP-receptor mediated changes in gene expression, signaling and chemotaxis. Results: This research successfully demonstrated three major findings. First, malignant or primary human T cells failed to differentially regulate any gene targets when treated with VIP ligand as assessed by an Agilent whole human microarray. Second, despite drastically different [cAMP]i profiles, both T cell lines responded similarly to VIP in Boyden Chamber assays showing both chemorepulsion and chemoattraction at low versus high VIP concentrations. Lastly, both T cell lines were equally sensitive to AC and PKA inhibitors that blocked VIP-induced chemotaxis, but were differentially sensitive to PKC inhibitors. Conclusion: Collectively, these results indicate that VIP signaling in resting human T cells is ineffective at altering mRNA expression changes, unlike their rodent counterparts, but can influence similar chemotactic effects, possibly through different signaling pathways elicited through VPAC1 versus VPAC2.

Background: The immortalized human epidermal keratinocytes HaCaT often serve as an experimental model of psoriasis. Previously, we reported that Th1 cytokines TNF, IFN-γ and IL17 suppressed proliferation in cultured HaCaT cells. Our results also suggested that at certain conditions, HaCaT cells could become susceptible to the named cytokines. Objective: The aim of this study was to analyze the consequences of FOSL1 silencing in HaCaT cells and explore the role of the transcription factor FOSL1 in the above mentioned antiproliferative effect. Methods: Lentiviral transduction was used to knock FOSL1 down in HaCaT cells. Changes in cell proliferation were assessed by analyzing the growth of transduced cells. Changes in gene expression were examined by qPCR. Results: We found that the treatment of FOSL1-deficient HaCaT cells with a combination of TNF, IFN-γ and IL17 led to growth arrest and apoptosis. In turn, exposure of these cells to the individual cytokines suggested that the presence of IFN-γ in the culture medium was the primary cause of cell death. FOSL1-deficient cells exposed to IFN-γ exhibited a dramatic shape change and intensive blebbing. Moreover, TNF and IL17 accelerated IFN-γ- induced apoptosis. A comparative analysis of gene expression in control and FOSL1- deficient HaCaT cells discovered that only TNF induced ten FOSL1 target genes previously implicated in the pathogenesis of psoriasis, namely CCL2, FOSL1, HMOX1, IL8, IL6, IVL, MGP, MMP1, MMP9, and PLAUR. In contrast, neither IFN-γ nor IL17 produced similar changes in the expression profiles of the mentioned genes. Conclusion: The obtained results suggest that the transcription factor FOSL1 protects HaCaT cells from apoptosis triggered by IFN-γ. This study also reveals distinct roles of Th1 cytokines in the regulation of FOSL1 target genes.