YB-1 orchestrates onset and resolution of renal inflammation via IL10 gene regulation.

Jialin Wang,Ina V Martin,Thomas Rauen,Peter Boor,Tammo Ostendorf,Daniel M Breitkopf,Lydia Gibbert,Jürgen Floege,Ute Raffetseder,Daniela Hermert,Vera Lennartz,Sonja Djudjaj,Gerald S Braun

doi:10.1111/jcmm.13260

Jialin Wang, Ina V Martin + Show 11 more

Open Access

https://doi.org/10.1111/jcmm.13260

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Abstract

The Y‐box‐binding protein (YB)‐1 plays a non‐redundant role in both systemic and local inflammatory response. We analysed YB‐1‐mediated expression of the immune regulatory cytokine IL‐10 in both LPS and sterile inflammation induced by unilateral renal ischaemia–reperfusion (I/R) and found an important role of YB‐1 not only in the onset but also in the resolution of inflammation in kidneys. Within a decisive cis‐regulatory region of the IL10 gene locus, the fourth intron, we identified and characterized an operative YB‐1 binding site via gel shift experiments and reporter assays in immune and different renal cells. In vivo, YB‐1 phosphorylated at serine 102 localized to the fourth intron, which was paralleled by enhanced IL‐10 mRNA expression in mice following LPS challenge and in I/R. Mice with half‐maximal expression of YB‐1 (Yb1 +/−) had diminished IL‐10 expression upon LPS challenge. In I/R, Yb1 +/− mice exhibited ameliorated kidney injury/inflammation in the early‐phase (days 1 and 5), however showed aggravated long‐term damage (day 21) with increased expression of IL‐10 and other known mediators of renal injury and inflammation.In conclusion, these data support the notion that there are context‐specific decisions concerning YB‐1 function and that a fine‐tuning of YB‐1, for example, via a post‐translational modification regulates its activity and/or localization that is crucial for systemic processes such as inflammation.

Highlights

The Y-box-binding protein (YB)-1 is a transcriptional and translational factor, which regulates many cellular processes such as cell proliferation, DNA repair, cellular stress response, cell differentiation, embryonic development and inflammation [1,2,3]
We unravel molecular mechanisms underlying YB-1induced IL-10 production during immune responses to microbial PAMPs as well as during ‘sterile’ inflammation and clarify the general capacity of YB-1 to mediate pro- and anti-inflammatory processes in these models in wild-type (WT) and Yb1+/À mice. As it controls IL-10 expression, we demonstrate that YB-1 orchestrates both onset and resolution of the inflammatory responses
Electrophoretic mobility supershift assays (EMSA) were performed with oligonucleotides that encompass the Y-box within the fourth intron of the human IL10 gene

Summary

Introduction

The YB-1 is a transcriptional and translational factor, which regulates many cellular processes such as cell proliferation, DNA repair, cellular stress response, cell differentiation, embryonic development and inflammation [1,2,3]. Systemic and localized inflammatory responses to infectious stimuli [4] as well as during ‘sterile’ inflammation [3, 4], YB-1 regulates expression of pro-inflammatory mediators. In the onset of inflammation, YB-1 up-regulates the expression of pro-inflammatory factors such as interleukin (IL)-6 [5] and CCL5 [4, 6,7,8]. Inflammatory events occur in the microvascular and tubulointerstitial compartment of the medulla with leukocytes and platelets blocking renal microcirculation.

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