Abstract
P38MAPK mediates cytokine induced inflammation in nucleus pulposus (NP) cells and involves in multiple cellular processes which are related to intervertebral disc degeneration (IDD). The aim of this study was to investigate the expression, activation and function of p38 MAPK isoforms (α,β, γ and δ) in degenerative NP and the effect of p38 activation in NP cells on macrophage polarization. P38 α, β and δ isoforms are preferential expressed, whereas the p38γ isoform is absent in human NP tissue. LV-sh-p38α, sh-p38β transfection in NP cells significantly decreased the ADAMTS-4,-5, MMP-13,CCL3 expression and restored collagen-II and aggrecan expression upon IL-1β stimulation. As compared with p38α and p38β, p38δ exhibited an opposite effect on ADAMTS-4,-5, MMP-13 and aggrecan expression in NP cells. Furthermore, the production of GM-CSF and IFNγ which were trigged by p38α or p38β in NP cells induced macrophage polarization into M1 phenotype. Our finding indicates that p38 MAPK α, β and δ isoform are predominantly expressed and activated in IDD. P38 positive NP cells modulate macrophage polarization through the production of GM-CSF and IFNγ. Hence, Our study suggests that selectively targeting p38 isoforms could ameliorate the inflammation in IDD and regard IDD progression.
Highlights
Low back pain (LBP) is one of the most popular health problems, and intervertebral disc degeneration (IDD) is thought to be a major cause for LBP1,2
It has been shown that macrophage polarization can be modulated by cytokines such as interferon γ (IFNγ, granulocyte-macrophage colony-stimulating factor (GM-CSF), TNF-α, IL-1β, and monocyte chemotactic protein-1 (MCP-1) which could be expressed by p38MAPK activated nucleus pulposus (NP) cells[28,29]
The expression of p38MAPK was significantly up-regulated in NP tissues compared to AF tissues as shown by western blot analysis of pooled extracts from 11 degenerated NPs tissues or 11 degenerated AFs tissues (Fig. 1B,E)
Summary
Low back pain (LBP) is one of the most popular health problems, and intervertebral disc degeneration (IDD) is thought to be a major cause for LBP1,2. To reduce the toxicity of p38MAPK inhibitor, a new strategy has been proposed that p38 isoforms should be selectively targeted based on its activation and function status in certain pathological conditions. Pro-inflammatory cytokines are increased in IDD, and p38MAPK mediates cytokine induced expression of catabolic enzymes, such as ADAMTS-4,-5 and MMPs in nucleus pulposus (NP) cells[17,18]. Our previous in vitro study have shown that upon cytokine stimulation, NP cells promotes macrophage migration by inducing the p38 MAPK mediated chemokine ligand 3 (CCL3) expression[25]. It has been shown that macrophage polarization can be modulated by cytokines such as interferon γ (IFNγ , granulocyte-macrophage colony-stimulating factor (GM-CSF), TNF-α , IL-1β , and monocyte chemotactic protein-1 (MCP-1) which could be expressed by p38MAPK activated NP cells[28,29]
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