Janus kinase activation by cytokine oncostatin M decreases PCSK9 expression in liver cells.

PCSK9 degrades LDL receptor (LDLR) in liver and thereby influences the circulating level of LDL cholesterol. Hence, mechanisms inhibiting PCSK9 expression have potential for cholesterol-lowering intervention. Previously, we demonstrated that oncostatin M (OM) activates LDLR gene transcription, resulting in an increased LDL uptake in HepG2 cells and a reduction of plasma LDL in hypercholesterolemic hamsters. Here we identify the suppression of PCSK9 expression by OM as one new mechanism that increases LDLR protein in HepG2 cells. Treating HepG2 cells with OM decreases PCSK9 mRNA and protein levels. Inhibition studies and small interfering RNA -targeted depletion revealed a critical role for JAK1 and JAK2 in mediating this OM inhibitory effect. Furthermore, we showed that OM induces transient phosphorylation of STAT1, STAT3, and STAT5 and sustained activation of ERK signaling molecules. While depletion of STAT members in HepG2 cells did not affect OM inhibitory activity on PCSK9 expression, blocking activation of the MEK1/ERK signaling pathway resulted in attenuation of the OM inhibitory effect. Finally, by using an anti-hamster PCSK9 antibody, we demonstrated the in vivo suppression of liver PCSK9 mRNA and protein expression by OM in hypercholesterolemic hamsters. Our study uncovered a cytokine-triggered regulatory network for PCSK9 expression that is linked to JAKs and the ERK signaling pathway.

Impaired antiviral activity of interferon alpha against hepatitis C virus 2a in Huh-7 cells with a defective Jak-Stat pathway.

BACKGROUND: The sustained virological response to interferon-alpha (IFN-alpha) in individuals infected with hepatitis C virus (HCV) genotype 1 is only 50%, but is about 80% in patients infected with genotype 2-6 viruses. The molecular mechanisms explaining the differences in IFN-alpha responsiveness between HCV 1 and other genotypes have not been elucidated. RESULTS: Virus and host cellular factors contributing to IFN responsiveness were analyzed using a green fluorescence protein (GFP) based replication system of HCV 2a and Huh-7 cell clones that either possesses or lack a functional Jak-Stat pathway. The GFP gene was inserted into the C-terminal non-structural protein 5A of HCV 2a full-length and sub-genomic clones. Both HCV clones replicated to a high level in Huh-7 cells and could be visualized by either fluorescence microscopy or flow cytometric analysis. Huh-7 cells transfected with the GFP tagged HCV 2a genome produced infectious virus particles and the replication of fluorescence virus particles was demonstrated in naïve Huh-7.5 cells after infection. IFN-alpha effectively inhibited the replication of full-length as well as sub-genomic HCV 2a clones in Huh-7 cells with a functional Jak-Stat pathway. However, the antiviral effect of IFN-alpha against HCV 2a virus was not observed in Huh-7 cell clones with a defect in Jak-Stat signaling. HCV infection or replication did not alter IFN-alpha induced Stat phosphorylation or ISRE promoter-luciferase activity in both the sensitive and resistant Huh-7 cell clones. CONCLUSIONS: The cellular Jak-Stat pathway is critical for a successful IFN-alpha antiviral response against HCV 2a. HCV infection or replication did not alter signaling by the Jak-Stat pathway. GFP labeled JFH1 2a replicon based stable cell lines with IFN sensitive and IFN resistant phenotypes can be used to develop new strategies to overcome IFN-resistance against hepatitis C.

Update on Janus kinase antagonists in inflammatory bowel disease.

Janus kinase (JAK) inhibitors have emerged as a novel orally administered small-molecule therapy for the treatment of ulcerative colitis and possibly Crohn disease. These molecules are designed to selectively target the activity of specific JAKs and to offer a targeted mechanism of action without risk of immunogenicity. Based on data from clinical trials in rheumatoid arthritis and phase 2 studies in inflammatory bowel disease, tofacitinib and other JAK inhibitors are likely to become a new form of medical therapy for the treatment of inflammatory bowel disease.

Jak/Stat signalling in niche support cells regulates dpp transcription to control germline stem cell maintenance in the Drosophila ovary.

The existence of specialised regulatory microenvironments or niches that sustain stable stem cell populations is well documented in many tissues. However, the specific mechanisms by which niche support (or stromal) cells govern stem cell maintenance remain largely unknown. Here we demonstrate that removal of the Jak/Stat pathway in support cells of the Drosophila ovarian niche leads to germline stem cell loss by differentiation. Conversely, ectopic Jak/Stat activation in support cells induces stem cell tumours, implying the presence of a signal relay between the stromal compartment and the stem cell population. We further show that ectopic Jak/Stat signalling in support cells augments dpp mRNA levels and increases the range of Dpp signalling, a Bmp2 orthologue known to act as a niche extrinsic factor required for female germline stem cell survival and division. Our results provide strong evidence for a model in which Jak/Stat signalling in somatic support cells regulates dpp transcription to define niche size and to maintain the adjacent germline stem cells in an undifferentiated state.