Mesencephalic astrocyte-derived neurotrophic factor is involved in inflammation by negatively regulating the NF-κB pathway

Lijian Chen; Lijie Feng; Xia Wang; Jian Du; Ying Chen; Wen Yang; Chengyue Zhou; Li Cheng; Yujun Shen; Shengyun Fang; Jun Li; Yuxian Shen

doi:10.1038/srep08133

Mesencephalic astrocyte-derived neurotrophic factor is involved in inflammation by negatively regulating the NF-κB pathway

Sci Rep. 2015 Feb 2:5:8133. doi: 10.1038/srep08133.

Authors

Lijian Chen¹, Lijie Feng², Xia Wang², Jian Du², Ying Chen³, Wen Yang⁴, Chengyue Zhou², Li Cheng², Yujun Shen², Shengyun Fang⁵, Jun Li⁶, Yuxian Shen²

Affiliations

¹ 1] School of Pharmacy, Anhui Medical University, Hefei 230032, Anhui, China [2] Institute of Biopharmaceuticals, Anhui Medical University, Hefei 230032, Anhui, China [3] Department of Anesthesiology of the First Affiliated Hospital, Anhui Medical University, Hefei 230022, Anhui, China.
² 1] School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui, China [2] Institute of Biopharmaceuticals, Anhui Medical University, Hefei 230032, Anhui, China.
³ Institute of Biopharmaceuticals, Anhui Medical University, Hefei 230032, Anhui, China.
⁴ 1] School of Pharmacy, Anhui Medical University, Hefei 230032, Anhui, China [2] Institute of Biopharmaceuticals, Anhui Medical University, Hefei 230032, Anhui, China.
⁵ 1] School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, Anhui, China [2] Institute of Biopharmaceuticals, Anhui Medical University, Hefei 230032, Anhui, China [3] Center for Biomedical Engineering and Technology, University of Maryland, Baltimore, MD 21201, USA.
⁶ School of Pharmacy, Anhui Medical University, Hefei 230032, Anhui, China.

Abstract

Inflammation can cause endoplasmic reticulum (ER) stress and therefore activates the unfolded protein response (UPR). ER stress and the consequent UPR have the potential to activate NF-κB. However, the factors mediating the crosstalk between ER stress and the NF-κB pathway remain unclear. Here, we determined that ER stress inducible protein Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) was up-regulated in autoimmune diseases and inflammatory disease models. Inflammation caused MANF to relocalize to the nuclei. MANF interacted with the DNA binding domain of p65 through its C-terminal SAP-like domain in the nuclei under the condition of inflammation or ER stress. MANF consequently inhibited p65-mediated transcriptional activation by interfering with the binding of p65 to its target genes promoters. Consistently, MANF suppressed the expressions of NF-κB-dependent target genes and the proliferation of inflammatory synoviocytes. These findings suggest that MANF may be a negative regulator of inflammation and mediate the crosstalk between the NF-κB pathway and ER stress.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Animals
Arthritis / chemically induced
Arthritis / metabolism
Arthritis / pathology
Cell Nucleus / metabolism
Cell Proliferation / drug effects
Cell Survival / drug effects
Cells, Cultured
Endoplasmic Reticulum Stress
Female
HEK293 Cells
Humans
Inflammation / metabolism
Inflammation / pathology*
Lupus Erythematosus, Systemic / metabolism
Lupus Erythematosus, Systemic / pathology
Male
Middle Aged
NF-kappa B / chemistry
NF-kappa B / metabolism*
Nerve Growth Factors / antagonists & inhibitors
Nerve Growth Factors / metabolism*
Nerve Growth Factors / pharmacology
Protein Binding
RNA, Small Interfering / metabolism
Rabbits
Rats
Recombinant Proteins / biosynthesis
Recombinant Proteins / genetics
Recombinant Proteins / pharmacology
Synovial Membrane / cytology
Synovial Membrane / drug effects
Synovial Membrane / metabolism
Transcription Factor RelA / chemistry
Transcription Factor RelA / genetics
Transcription Factor RelA / metabolism
Transcriptional Activation
Tumor Necrosis Factor-alpha / pharmacology

Substances

NF-kappa B
Nerve Growth Factors
RNA, Small Interfering
Recombinant Proteins
Transcription Factor RelA
Tumor Necrosis Factor-alpha