title: Differential expression of p38 MAPK α, β, γ, δ isoforms in nucleus pulposus modulates macrophage polarization in intervertebral disc degeneration.
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.
authors.affiliation: Department of orthopedic Surgery, Changzheng Hospital, Shanghai 200003, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of orthopedic Surgery, Changzheng Hospital, Shanghai 200003, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Cao
authors.affiliation: Department of orthopedic Surgery, Changzheng Hospital, Shanghai 200003, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Kidney Institute, Department of Nephrology, Changzheng Hospital, Shanghai 200003, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Wu
authors.affiliation: National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of orthopedic Surgery, Changzheng Hospital, Shanghai 200003, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
authors.affiliation: Department of orthopedic Surgery, Changzheng Hospital, Shanghai 200003, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Yuan
mesh_terms: D000071096:ADAMTS Proteins / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D002454:Cell Differentiation; D054405:Chemokine CCL3 / Q000235:genetics / Q000378:metabolism; D024043:Collagen Type II / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D055959:Intervertebral Disc Degeneration / Q000276:immunology*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D000070614:Nucleus Pulposus / Q000166:cytology / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D054405:Chemokine CCL3; D024043:Collagen Type II; D053583:Interleukin-1beta; D007527:Isoenzymes; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D048051:p38 Mitogen-Activated Protein Kinases; D000071096:ADAMTS Proteins; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13