Exp Mol Med.  2017 Sep;49(9):e379. 10.1038/emm.2017.136.

TGF-β1 suppresses CCL3/4 expression through the ERK signaling pathway and inhibits intervertebral disc degeneration and inflammation-related pain in a rat model

• Zhang J
• Li Z
• Chen F
• Liu H
• Wang H
• Li X
• Liu X
• Wang J
• Zheng Z

• KMID: 2394310
• DOI: http://doi.org/10.1038/emm.2017.136

Abstract

The objective of this study was to investigate the regulatory effects of TGF-β1 on CCL3/4 expression and inflammation-related pain during intervertebral disc degeneration (IVDD). TGF-β1 and CCL3/4 expression patterns in different degenerative human nucleus pulposus (NP) tissues were measured by qPCR and immunohistochemistry (IHC), and the effects of TGF-β1 on CCL3/4 expression were measured by qPCR, ELISA and immunofluorescence. The roles of NF-κB and MAPK in TGF-β1-mediated CCL3/4 promoter activity were studied using siRNAs, western blotting and qPCR. After establishing an IVDD rat model in vivo, we administered intradiscal injections of TGF-β1. The effects of TGF-β1 on IVDD were determined by MRI and histological analyses, and the effects of TGF-β1 on dorsal root ganglion (DRG) inflammation and pain development were determined by IHC staining and pain-behavior testing, respectively. TGF-β1 and CCL3/4 expression was elevated in degenerative NP tissue. CCL4 expression was significantly inhibited by TGF-β1 treatment. Pharmacological inhibition or siRNA knockdown of the ERK1/2 signaling attenuated TGF-β1-mediated suppression of CCL4 expression. In vivo, TGF-β1 injection inhibited the development of degenerative features in the IVDD model. Moreover, TGF-β1 prevented the inflammatory response and pain development. The results of this study show that TGF-β1 downregulates CCL4 expression through ERK1/2 signaling activation in NP cells. Furthermore, TGF-β1 can prevent degenerative processes, inhibit inflammatory responses in the DRG and prevent pain development in the IVDD rat model. The results of this study indicate that TGF-β1 may represent a therapeutic target for the control of inflammation-related pain associated with IVDD.

MeSH Terms

Animals
Blotting, Western
Diagnosis-Related Groups
Enzyme-Linked Immunosorbent Assay
Fluorescent Antibody Technique
Ganglia, Spinal
Humans
Immunohistochemistry
Inflammation
Intervertebral Disc Degeneration*
Intervertebral Disc*
Magnetic Resonance Imaging
Models, Animal*
Rats*
RNA, Small Interfering
RNA, Small Interfering