Resveratrol Protects Human Nucleus Pulposus Cells from Degeneration by Blocking IL-6/JAK/STAT3 Pathway

Abstract

Background: Nucleus pulposus cells’ (NPCs’) degeneration is mainly responsible for the intervertebral disc degeneration (IDD), which is closely related to inflammatory response. Among the major proinflammatory factors that are related to NPCs’ degeneration, interleukin-6 (IL-6) and its downstream JAK/STAT3 pathway have received recent attention. The goal of our study is to figure out whether or how resveratrol (RSV) can protect NPCs from degeneration by affecting IL6/JAK/STAT3 pathway. Methods: Different concentrations of RSV were added to NPCs’ mediums. Cell viability was measured by MTT assay and crystal violet staining. Cell cycle and apoptosis were analyzed by flow cytometry. Protein expression level was determined by western blot. mRNA expression level was measured by qPCR.Results: Our study showed that RSV improved NPCs’ cell viability. It also inhibited cell apoptosis and cell cycle arrest, which were accompanied by the increased expression level of heat shock protein 90 (HSP90) and N-Cadherin. What’ more, RSV also improved the NPCs’ degeneration which was reflected in the increase of extracellular matrix (collagen II, Aggrecan). Moreover, RSV significantly attenuated the level of IL-6 secretion, which was accompanied by less phosphorylation of the transcription factors janus kinase 1 (JAK1) and signal transducer and activator of transcription 3 (STAT3). Conclusion: RSV exerted its protective effect on HNPCs’ degeneration by improving cell survival and function. The possible mechanism may be associated with the suppression of JAK/STAT3 phosphorylation and the decreased IL-6 production, which could be explained by a blockage of the positive feedback control loop between IL-6 and JAK/STAT3 pathway.

Anemonin attenuates hydrogen peroxide-induced oxidative stress, inflammation and extracellular matrix degradation in nucleus pulposus cells by regulating NOX4/NF-κB signaling pathway

“…IL-6 could aggregate in ammatory cells, regulate the overexpression of matrix metallolytic enzymes, promote the degeneration of extracellular matrix, and enhance IVDD (41). It was found that resveratrol improved NPCs growth and degeneration of extracellular matrix by IL-6/JAK/STAT3 pathway (42). The study have con rmed that IL-1β and TNF-α are highly expressed in IVDD tissues compared with normal intervertebral disc tissues (43).…”

Periplocymarin alleviates pathological cardiac hypertrophy via inhibiting the JAK2/STAT3 signalling pathway

“…It has been reported that once STAT3 is activated via phosphorylation, STAT3 forms dimers to interact with the reciprocal phosphotyrosine‐SH2 domain, which quickly translocate to the nucleus, where STAT3 binds to DNA and induces the expression of target genes 15,20 . Hence, STAT3 distribution in the nuclear and cytosolic fractions was analysed.…”

“…It has been reported that once STAT3 is activated via phosphorylation, STAT3 forms dimers to interact with the reciprocal phosphotyrosine-SH2 domain, which quickly translocate to the nucleus, where STAT3 binds to DNA and induces the expression of target genes. 15,20 Hence, STAT3 distribution in the nuclear and cytosolic fractions was analysed. As shown in Figure 3A TAC-induced mice displayed a significant increase in heart mass, while the ratios of heart weight to body weight (HW/BW) and heart weight to tibial length (HW/TL) were reduced following treatment with PM (Table 1).…”

“…Modern pharmacological studies have established that the JAK2/STAT3 signalling pathway participates in the progression of myocardial ischaemia, cardiac hypertrophy and heart failure 17–19 . STAT3, a key transcription factor in this pathway, can be recruited and phosphorylated by JAK2, and the phosphorylated STAT3 protein can enter the nucleus as a dimer and bind with the target gene to regulate the transcription of downstream genes 15,20 . Recent research has revealed that cardiac hypertrophy can be effectively improved by inhibiting the activation of the JAK/STAT3 signalling pathway using STAT3 inhibitors or silencing the STAT3 gene 14,21,22 …”

“…[17][18][19] STAT3, a key transcription factor in this pathway, can be recruited and phosphorylated by JAK2, and the phosphorylated STAT3 protein can enter the nucleus as a dimer and bind with the target gene to regulate the transcription of downstream genes. 15,20 Recent research has revealed that cardiac hypertrophy can be effectively improved by inhibiting the activation of the JAK/STAT3 signalling pathway using STAT3 inhibitors or silencing the STAT3 gene. 14,21,22 Therefore, STAT3 is regarded as a novel therapeutic target for delaying and reducing the progression from cardiac hypertrophy to chronic heart failure.…”