Abstract
The aim of the article was to study the mechanism of Lipoxin A4 (LXA4)-mediated p38 MAPK pathway protecting mice against collagen-induced arthritis (CIA). The impact of LXA4 (0, 5, 10, 15 nM) on synoviocytes proliferation of CIA mice was detected using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. CIA mice were treated with LXA4, SB203580 (a p38 inhibitor), and/or anisomycin (a p38 agonist), and the arthritis severity score in each mouse was determined. The gene or protein expressions were detected with Western Blotting, ELISA, or qRT-PCR. LXA4 inhibited the synoviocytes proliferation of CIA mice with decreased levels of TNF-α, IL-6, IL-1β, and IFN-γ and reduced p-p38/total p38 expression in synoviocytes in a dose-dependent manner. LXA4 levels were decreased in synovial tissues and plasma of CIA mice, but p-p38/total p38 expression was increased in synovial tissues. LXA4 could downregulate p-p38/total p38 expression in synovial tissues of CIA mice. Both LXA4 and SB203580 reduced arthritis severity score of CIA mice with the reduction of synovial tissue hyperplasia and inflammatory cell infiltration. CIA mice treated with LXA4 and SB203580 had lower levels of TNF-α, IL-6, IL-1β, and IFN-γ, accompanying decreased MDA as well as increased SOD, CAT,and GPx. However, anisomycin could reverse the protect effects of LXA4 on CIA mice regarding the abovementioned inflammatory factors and oxidative stress indexes. LXA4 protected mice against collagen-induced arthritis via inhibiting p38 MAPK signaling pathway, which may be a potential new therapeutic target for rheumatoid arthritis.
Similar content being viewed by others
References
An Y et al (2017) The usage of biological DMARDs and clinical remission of rheumatoid arthritis in China: a real-world large scale study. Clin Rheumatol 36:35–43. https://doi.org/10.1007/s10067-016-3424-5
Blais C Jr, Couture R, Drapeau G, Colman RW, Adam A (1997) Involvement of endogenous kinins in the pathogenesis of peptidoglycan-induced arthritis in the Lewis rat. Arthritis Rheum 40:1327–1333. https://doi.org/10.1002/1529-0131(199707)40:7%3c1327::AID-ART18%3e3.0.CO;2-B
Bonnans C, Vachier I, Chavis C, Godard P, Bousquet J, Chanez P (2002) Lipoxins are potential endogenous antiinflammatory mediators in asthma. Am J Respir Crit Care Med 165:1531–1535. https://doi.org/10.1164/rccm.200201-053OC
Borgeson E et al (2012) Lipoxin A4 attenuates adipose inflammation. FASEB J 26:4287–4294. https://doi.org/10.1096/fj.12-208249
Brady HR, Serhan CN (1996) Lipoxins: putative braking signals in host defense, inflammation and hypersensitivity. Curr Opin Nephrol Hypertens 5:20–27
Chagas PM, Fulco BCW, Sari MHM, Roehrs JA, Nogueira CW (2017) Bis(phenylimidazoselenazolyl) diselenide elicits antinociceptive effect by modulating myeloperoxidase activity, NOx and NFkB levels in the collagen-induced arthritis mouse model. J Pharm Pharmacol 69:1022–1032. https://doi.org/10.1111/jphp.12738
Chen XQ, Wu SH, Zhou Y, Tang YR (2013) Lipoxin A4-induced heme oxygenase-1 protects cardiomyocytes against hypoxia/reoxygenation injury via p38 MAPK activation and Nrf2/ARE complex. PLoS ONE 8:e67120. https://doi.org/10.1371/journal.pone.0067120
Cheng Q et al (2016) Lipoxin A4 protects against lipopolysaccharide-induced sepsis by promoting innate response activator B cells generation. Int Immunopharmacol 39:229–235. https://doi.org/10.1016/j.intimp.2016.07.026
Conte FP, Menezes-de-Lima O Jr, Verri WA Jr, Cunha FQ, Penido C, Henriques MG (2010) Lipoxin A(4) attenuates zymosan-induced arthritis by modulating endothelin-1 and its effects. Br J Pharmacol 161:911–924. https://doi.org/10.1111/j.1476-5381.2010.00950.x
Criado G, Risco A, Alsina-Beauchamp D, Perez-Lorenzo MJ, Escos A, Cuenda A (2014) Alternative p38 MAPKs are essential for collagen-induced arthritis. Arthritis Rheumatol 66:1208–1217. https://doi.org/10.1002/art.38327
Dai S et al (2019) Lipoxin A4 suppresses IL-1beta-induced cyclooxygenase-2 expression through inhibition of p38 MAPK activation in endometriosis. Reprod Sci. https://doi.org/10.1177/1933719119828115
Derk CT (2005) Rheumatoid arthritis: an update. Del Med J 77:59–63
Durie FH, Fava RA, Noelle RJ (1994) Collagen-induced arthritis as a model of rheumatoid arthritis. Clin Immunol Immunopathol 73:11–18. https://doi.org/10.1006/clin.1994.1164
Ebru U et al (2008) Cardioprotective effects of Nigella sativa oil on cyclosporine A-induced cardiotoxicity in rats. Basic Clin Pharmacol Toxicol 103:574–580. https://doi.org/10.1111/j.1742-7843.2008.00313.x
Fierro IM, Kutok JL, Serhan CN (2002) Novel lipid mediator regulators of endothelial cell proliferation and migration: aspirin-triggered-15R-lipoxin A(4) and lipoxin A(4). J Pharmacol Exp Ther 300:385–392. https://doi.org/10.1124/jpet.300.2.385
Fiore S, Antico G, Aloman M, Sodin-Semrl S (2005) Lipoxin A4 biology in the human synovium. Role of the ALX signaling pathways in modulation of inflammatory arthritis. Prostaglandins Leukotrienes Essential Fatty Acids 73:189–196. https://doi.org/10.1016/j.plefa.2005.05.005
Gao S, Qi X, Li J, Sang L (2017) Upregulated KAT7 in synovial fibroblasts promotes Th17 cell differentiation and infiltration in rheumatoid arthritis. Biochem Biophys Res Commun 489:235–241. https://doi.org/10.1016/j.bbrc.2017.05.143
Garate D et al (2013) Blocking of p38 and transforming growth factor beta receptor pathways impairs the ability of tolerogenic dendritic cells to suppress murine arthritis. Arthritis Rheum 65:120–129. https://doi.org/10.1002/art.37702
Gierman LM et al (2013) Metabolic profiling reveals differences in concentrations of oxylipins and fatty acids secreted by the infrapatellar fat pad of donors with end-stage osteoarthritis and normal donors. Arthritis Rheum 65:2606–2614. https://doi.org/10.1002/art.38081
Grumbach Y, Quynh NV, Chiron R, Urbach V (2009) LXA4 stimulates ZO-1 expression and transepithelial electrical resistance in human airway epithelial (16HBE14o-) cells. Am J Physiol Lung Cell Mol Physiol 296:L101-108. https://doi.org/10.1152/ajplung.00018.2008
Guo YP, Jiang HK, Jiang H, Tian HY, Li L (2018) Lipoxin A4 may attenuate the progression of obesity-related glomerulopathy by inhibiting NF-kappaB and ERK/p38 MAPK-dependent inflammation. Life Sci 198:112–118. https://doi.org/10.1016/j.lfs.2018.02.039
Habouri L et al (2017) Deletion of 12/15-lipoxygenase accelerates the development of aging-associated and instability-induced osteoarthritis. Osteoarthritis Cartilage 25:1719–1728. https://doi.org/10.1016/j.joca.2017.07.001
Han X, Yao W, Liu Z, Li H, Zhang ZJ, Hei Z, Xia Z (2016) Lipoxin A4 preconditioning attenuates intestinal ischemia reperfusion injury through Keap1/Nrf2 pathway in a lipoxin A4 receptor independent manner. Oxid Med Cell Longev 2016:9303606. https://doi.org/10.1155/2016/9303606
Jonsson H, Allen P, Peng SL (2005) Inflammatory arthritis requires Foxo3a to prevent Fas ligand-induced neutrophil apoptosis. Nat Med 11:666–671. https://doi.org/10.1038/nm1248
Ju JH et al (2008) Oral administration of type-II collagen suppresses IL-17-associated RANKL expression of CD4+ T cells in collagen-induced arthritis. Immunol Lett 117:16–25. https://doi.org/10.1016/j.imlet.2007.09.011
Kanashiro A et al (2018) Inhibition of spinal p38 MAPK prevents articular neutrophil infiltration in experimental arthritis via sympathetic activation. Fundam Clin Pharmacol 32:155–162. https://doi.org/10.1111/fcp.12338
Kauss T et al (2008) Rutoside decreases human macrophage-derived inflammatory mediators and improves clinical signs in adjuvant-induced arthritis. Arthritis Res Ther 10:R19. https://doi.org/10.1186/ar2372
Kraan MC, Haringman JJ, Ahern MJ, Breedveld FC, Smith MD, Tak PP (2000) Quantification of the cell infiltrate in synovial tissue by digital image analysis. Rheumatology 39:43–49. https://doi.org/10.1093/rheumatology/39.1.43
Kronke G et al (2009) 12/15-lipoxygenase counteracts inflammation and tissue damage in arthritis. J Immunol 183:3383–3389. https://doi.org/10.4049/jimmunol.0900327
Liao W et al (2013) Lipoxin A4 attenuates acute rejection via shifting TH1/TH2 cytokine balance in rat liver transplantation. Transplant Proc 45:2451–2454. https://doi.org/10.1016/j.transproceed.2013.01.069
Lu T, Zong M, Fan S, Lu Y, Yu S, Fan L (2018) Thioredoxin 1 is associated with the proliferation and apoptosis of rheumatoid arthritis fibroblast-like synoviocytes. Clin Rheumatol 37:117–125. https://doi.org/10.1007/s10067-017-3832-1
Luo CL et al (2013) Lipoxin A4 attenuates brain damage and downregulates the production of pro-inflammatory cytokines and phosphorylated mitogen-activated protein kinases in a mouse model of traumatic brain injury. Brain Res 1502:1–10. https://doi.org/10.1016/j.brainres.2013.01.037
Lv W et al (2013) Lipoxin A4 attenuation of endothelial inflammation response mimicking pancreatitis-induced lung injury. Exp Biol Med 238:1388–1395. https://doi.org/10.1177/1535370213502611
Martinez RM et al (2018) Lipoxin A4 inhibits UV radiation-induced skin inflammation and oxidative stress in mice. J Dermatol Sci. https://doi.org/10.1016/j.jdermsci.2018.04.014
McMahon B, Mitchell D, Shattock R, Martin F, Brady HR, Godson C (2002) Lipoxin, leukotriene, and PDGF receptors cross-talk to regulate mesangial cell proliferation. FASEB J 16:1817–1819. https://doi.org/10.1096/fj.02-0416fje
Ni S et al (2018) Follistatin-like protein 1 induction of matrix metalloproteinase 1, 3 and 13 gene expression in rheumatoid arthritis synoviocytes requires MAPK, JAK/STAT3 and NF-kappaB pathways. J Cell Physiol 234:454–463. https://doi.org/10.1002/jcp.26580
Okada T et al (2010) Synoviocyte-derived angiopoietin-like protein 2 contributes to synovial chronic inflammation in rheumatoid arthritis. Am J Pathol 176:2309–2319. https://doi.org/10.2353/ajpath.2010.090865
Ozgul Ozdemir RB, Soysal Gunduz O, Ozdemir AT, Akgul O (2020) Low levels of pro-resolving lipid mediators lipoxin-A4, resolvin-D1 and resolvin-E1 in patients with rheumatoid arthritis. Immunol Lett 227:34–40. https://doi.org/10.1016/j.imlet.2020.08.006
Pretorius E, Akeredolu OO, Soma P, Kell DB (2017) Major involvement of bacterial components in rheumatoid arthritis and its accompanying oxidative stress, systemic inflammation and hypercoagulability. Exp Biol Med (Maywood) 242:355–373. https://doi.org/10.1177/1535370216681549
Sodin-Semrl S, Spagnolo A, Barbaro B, Varga J, Fiore S (2004) Lipoxin A4 counteracts synergistic activation of human fibroblast-like synoviocytes. Int J Immunopathol Pharmacol 17:15–25. https://doi.org/10.1177/039463200401700103
Song Y, Yang Y, Cui Y, Gao J, Wang K, Cui J (2019) Lipoxin A4 methyl ester reduces early brain injury by inhibition of the nuclear factor kappa B (NF-kappaB)-dependent matrix metallopeptidase 9 (MMP-9) pathway in a rat model of intracerebral hemorrhage medical science monitor. Int Med J Exp Clin Res 25:1838–1847. https://doi.org/10.12659/MSM.915119
Szanto S, Bardos T, Gal I, Glant TT, Mikecz K (2004) Enhanced neutrophil extravasation and rapid progression of proteoglycan-induced arthritis in TSG-6-knockout mice. Arthritis Rheum 50:3012–3022. https://doi.org/10.1002/art.20655
Tak PP, Zvaifler NJ, Green DR, Firestein GS (2000) Rheumatoid arthritis and p53: how oxidative stress might alter the course of inflammatory diseases. Immunol Today 21:78–82
Trentham DE, Townes AS, Kang AH (1977) Autoimmunity to type II collagen an experimental model of arthritis. J Exp Med 146:857–868. https://doi.org/10.1084/jem.146.3.857
Trovato A et al (2016a) Redox modulation of cellular stress response and lipoxin A4 expression by Coriolus versicolor in rat brain: Relevance to Alzheimer’s disease pathogenesis. Neurotoxicology 53:350–358. https://doi.org/10.1016/j.neuro.2015.09.012
Trovato A et al (2016b) Redox modulation of cellular stress response and lipoxin A4 expression by Hericium Erinaceus in rat brain: relevance to Alzheimer’s disease pathogenesis. Immunity Ageing 13:23. https://doi.org/10.1186/s12979-016-0078-8
Villa-Diaz LG, Miyano T (2004) Activation of p38 MAPK during porcine oocyte maturation. Biol Reprod 71:691–696. https://doi.org/10.1095/biolreprod.103.026310
Wang QH et al (2017) Pharmacological Effect of Caulophyllum robustum on Collagen-Induced Arthritis and Regulation of Nitric Oxide NF-kappaB, and Proinflammatory Cytokines. In Vivo In Vitro Evid-Based Complement Altern Med 2017:8134321. https://doi.org/10.1155/2017/8134321
Wang X et al (2019) Losartan suppresses the inflammatory response in collagen-induced arthritis by inhibiting the MAPK and NF-kappaB pathways in B and T cells. Inflammopharmacology 27:487–502. https://doi.org/10.1007/s10787-018-0545-2
National Institutes of Health (2011) Guide for the care and use of laboratory animals. The National Academies Collection: Reports. National Institutes of Health, Washington (DC)
Wedekind KJ, Ruff KJ, Atwell CA, Evans JL, Bendele AM (2017) Beneficial effects of natural eggshell membrane (NEM) on multiple indices of arthritis in collagen-induced arthritic rats. Mod Rheumatol 27:838–848. https://doi.org/10.1080/14397595.2016.1259729
Wu SH, Lu C, Dong L, Zhou GP, He ZG, Chen ZQ (2005) Lipoxin A4 inhibits TNF-alpha-induced production of interleukins and proliferation of rat mesangial cells. Kidney Int 68:35–46. https://doi.org/10.1111/j.1523-1755.2005.00379.x
Wu R et al (2014) Lipoxin A4 suppresses the development of endometriosis in an ALX receptor-dependent manner via the p38 MAPK pathway. Br J Pharmacol 171:4927–4940. https://doi.org/10.1111/bph.12816
Xia ZB et al (2018) Inhibition of NF-kappaB signaling pathway induces apoptosis and suppresses proliferation and angiogenesis of human fibroblast-like synovial cells in rheumatoid arthritis. Medicine (Baltimore) 97:e10920. https://doi.org/10.1097/MD.0000000000010920
Yang ZH et al (2016) Targeting P38 pathway regulates bony formation via MSC recruitment during mandibular distraction osteogenesis in rats. Int J Med Sci 13:783–789. https://doi.org/10.7150/ijms.16663
Yang S, Zheng Y, Hou X (2019) Lipoxin A4 restores oxidative stress-induced vascular endothelial cell injury and thrombosis-related factor expression by its receptor-mediated activation of Nrf2-HO-1 axis. Cell Signal 60:146–153. https://doi.org/10.1016/j.cellsig.2019.05.002
Zerbini CAF et al (2017) Biologic therapies and bone loss in rheumatoid arthritis. Osteoporos Int 28:429–446. https://doi.org/10.1007/s00198-016-3769-2
Zheng S et al (2016) Lipoxin A4 promotes lung epithelial repair whilst inhibiting fibroblast proliferation. ERJ Res. Open 2:0095. https://doi.org/10.1183/23120541.00079-2015
Acknowledgements
This study was supported by Beijing University of Traditional Chinese Medicine Dongzhimen Hospital Youth Talent Project (NO: DZMYY-201802) and Chinese Traditional Medicine Association Young Talents Lifting Project (NO: NQRC2-C08).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interests
The authors declare that they have no conflicts of interests..
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Jinyu Li and Qi Sun are co-first authors.
Rights and permissions
About this article
Cite this article
Li, J., Sun, Q., Zheng, C. et al. Lipoxin A4-Mediated p38 MAPK Signaling Pathway Protects Mice Against Collagen-Induced Arthritis. Biochem Genet 59, 346–365 (2021). https://doi.org/10.1007/s10528-020-10016-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10528-020-10016-9