Inflammation Regulates TMPRSS6 Expression via STAT5

Delphine Meynard,Herbert Y Lin,Jodie L Babitt,Qifang Wu,Caroline N Nelson,Chia Chi Sun,Michael J Waters,Wenjie Chen,Shanzhuo Chen,Shannon M Hawkins

doi:10.1371/journal.pone.0082127

Abstract

TMPRSS6 is a regulated gene, with a crucial role in the regulation of iron homeostasis by inhibiting hepcidin expression. The main regulator of iron homeostasis, the antimicrobial peptide hepcidin, which also has a role in immunity, is directly upregulated by inflammation. In this study, we analyzed whether inflammation is also a modulator of TMPRSS6 expression in vitro and in vivo and we determined the mechanism of this regulation A Human Hepatoma cell line was treated with interleukin-6 and mice were injected with lipopolysaccharide and TMPRSS6 expression and the regulatory mechanism were addressed. In this study, we demonstrate that inflammation downregulates TMPRSS6 expression in vitro and in vivo. The downregulation of Tmprss6 by inflammation in mice is not dependent on the Bmp-Smad pathway but occurs through a decrease in Stat5 phosphorylation. Moreover, Stat5 positively regulates Tmprss6 expression directly by binding to a Stat5 element located on the Tmprss6 promoter. Importantly, our results highlight the functional role of inflammatory modulation of TMPRSS6 expression in the regulation of hepcidin. TMPRSS6 inhibition via decreased STAT5 phosphorylation may be an additional mechanism by which inflammation stimulates hepcidin expression to regulate iron homeostasis and immunity.

Highlights

The transmembrane serine protease matriptase-2, encoded by the TMPRSS6 gene, is expressed in the liver and is a negative regulator of hepcidin expression [1]
To test whether IL-6 treatment could modulate TMPRSS6 mRNA expression in vitro, human hepatoma-derived Hep3B cells were treated with increasing doses of IL-6, and HAMP and TMPRSS6 mRNA expression was evaluated by quantitative realtime PCR
We identified a novel pathway for hepcidin regulation by inflammation via TMPRSS6 and STAT5 that is independent of the previously described STAT3 and BMP-SMAD pathways

Summary

Introduction

The transmembrane serine protease matriptase-2, encoded by the TMPRSS6 gene, is expressed in the liver and is a negative regulator of hepcidin expression [1]. The importance of TMPRSS6 in the control of iron homeostasis and normal erythropoiesis in humans has been highlighted by genome-wide association studies. These studies identified common TMPRSS6 variants associated with hematological parameters and serum iron concentration [3]. It is well established that hepcidin expression is regulated by the BMP-SMAD pathway in response to iron variation [5]. Mutated forms of matriptase-2 are unable to cleave membrane hemojuvelin [6], resulting in a stimulation of the BMP-SMAD signaling pathway and an inappropriately high hepcidin expression

Methods

Results

Conclusion