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MAPK/p38 regulation of cytoskeleton rearrangement accelerates induction of macrophage activation by TLR4, but not TLR3

  • Authors:
    • Hongjun Bian
    • Feifei Li
    • Wenwen Wang
    • Qi Zhao
    • Shanshan Gao
    • Jincai Ma
    • Xiao Li
    • Wanhua Ren
    • Chengyong Qin
    • Jianni Qi
  • View Affiliations / Copyright

    Affiliations: Department of Emergency Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China, Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China, Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China
    Copyright: © Bian et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 1495-1503
    |
    Published online on: September 19, 2017
       https://doi.org/10.3892/ijmm.2017.3143
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Abstract

Toll-like receptor 3 (TLR3) and TLR4 utilize adaptor proteins to activate mitogen‑activated protein kinase (MAPK), resulting in the acute but transient inflammatory response aimed at the clearance of pathogens. In the present study, it was demonstrated that macrophage activation by lipopolysaccharide (LPS) or poly(I:C), leading to changes in cell morphology, differed significantly between the mouse macrophage cell line RAW264.7 and mouse primary peritoneal macrophages. Moreover, the expression of α- and β-tubulin was markedly decreased following LPS stimulation. By contrast, α- and β-tubulin expression were only mildly increased following poly(I:C) treatment. However, the expression of β-actin and GAPDH was not significantly affected. Furthermore, it was verified that vincristine pretreatment abrogated the cytoskeleton rearrangement and decreased the synthesis and secretion of proinflammatory cytokines and migration of macrophages caused by LPS. Finally, it was observed that the MAPK/p38 signaling pathway regulating cytoskeleton rearrangement may participate in LPS‑induced macrophage cytokine production and migration. Overall, the findings of the present study indicated that MAPK/p38 regulation of the cytoskeleton, particularly tubulin proteins, plays an important role in LPS-induced inflammatory responses via alleviating the synthesis and secretion of proinflammatory cytokines and inhibiting the migration of macrophages.
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1 

Pelka K, Shibata T, Miyake K and Latz E: Nucleic acid-sensing TLRs and autoimmunity: Novel insights from structural and cell biology. Immunol Rev. 269:60–75. 2016. View Article : Google Scholar

2 

Kawai T and Akira S: The role of pattern-recognition receptors in innate immunity: Update on Toll-like receptors. Nat Immunol. 11:373–384. 2010. View Article : Google Scholar : PubMed/NCBI

3 

Zhao W, Qi J, Wang L, Zhang M, Wang P and Gao C: LY294002 inhibits TLR3/4-mediated IFN-β production via inhibition of IRF3 activation with a PI3K-independent mechanism. FEBS Lett. 586:705–710. 2012. View Article : Google Scholar : PubMed/NCBI

4 

Bosshart H and Heinzelmann M: Targeting bacterial endotoxin: Two sides of a coin. Ann NY Acad Sci. 1096:1–17. 2007. View Article : Google Scholar : PubMed/NCBI

5 

Kustermans G, Piette J and Legrand-Poels S: Actin-targeting natural compounds as tools to study the role of actin cytoskeleton in signal transduction. Biochem Pharmacol. 76:1310–1322. 2008. View Article : Google Scholar : PubMed/NCBI

6 

Diesel B, Hoppstädter J, Hachenthal N, Zarbock R, Cavelius C, Wahl B, Thewes N, Jacobs K, Kraegeloh A and Kiemer AK: Activation of Rac1 GTPase by nanoparticulate structures in human macrophages. Eur J Pharm Biopharm. 84:315–324. 2013. View Article : Google Scholar : PubMed/NCBI

7 

Song W, Liu C and Upadhyaya A: The pivotal position of the actin cytoskeleton in the initiation and regulation of B cell receptor activation. Biochim Biophys Acta. 1838:569–578. 2014. View Article : Google Scholar

8 

Chen YR, Feng F, Wang L, Qu SY, Zhang ZQ, Liu L, Qin HY, Liang YM and Han H: Deletion of RBP-j in dendritic cells compromises TLR-mediated DC activation accompanied by abnormal cytoskeleton reorganization. Mol Biol Rep. 40:1531–1539. 2013. View Article : Google Scholar

9 

Moudi M, Go R, Yien CY and Nazre M: Vinca alkaloids. Int J Prev Med. 4:1231–1235. 2013.

10 

Pathak P, Hess R and Weiss MA: Liposomal vincristine for relapsed or refractory Ph-negative acute lymphoblastic leukemia: A review of literature. Ther Adv Hematol. 5:18–24. 2014. View Article : Google Scholar : PubMed/NCBI

11 

Thakur V, Kush P, Pandey RS, Jain UK, Chandra R and Madan J: Vincristine sulfate loaded dextran microspheres amalgamated with thermosensitive gel offered sustained release and enhanced cytotoxicity in THP-1, human leukemia cells: In vitro and in vivo study. Mater Sci Eng C. 61:113–122. 2016. View Article : Google Scholar

12 

Ruiz-Gómez MJ, Souviron A, Martínez-Morillo M and Gil L: P-glycoprotein, glutathione and glutathione S-transferase increase in a colon carcinoma cell line by colchicine. J Physiol Biochem. 56:307–312. 2000. View Article : Google Scholar

13 

Qi J, Qiao Y, Wang P, Li S, Zhao W and Gao C: microRNA-210 negatively regulates LPS-induced production of proinflammatory cytokines by targeting NF-κB1 in murine macrophages. FEBS Lett. 586:1201–1207. 2012. View Article : Google Scholar : PubMed/NCBI

14 

Qi J, Li T, Bian H, Li F, Ju Y, Gao S, Su J, Ren W and Qin C: SNAI1 promotes the development of HCC through the enhancement of proliferation and inhibition of apoptosis. FEBS Open Bio. 6:326–337. 2016. View Article : Google Scholar : PubMed/NCBI

15 

Wu J, Zhang H, Hu B, Yang L, Wang P, Wang F and Meng X: Coptisine from Coptis chinensis inhibits production of inflammatory mediators in lipopolysaccharide-stimulated RAW264.7 murine macrophage cells. Eur J Pharmacol. 780:106–114. 2016. View Article : Google Scholar : PubMed/NCBI

16 

Bode KA, Schmitz F, Vargas L, Heeg K and Dalpke AH: Kinetic of RelA activation controls magnitude of TLR-mediated IL-12p40 induction. J Immunol. 182:2176–2184. 2009. View Article : Google Scholar : PubMed/NCBI

17 

Devisscher L, Verhelst X, Colle I, Van Vlierberghe H and Geerts A: The role of macrophages in obesity-driven chronic liver disease. J Leukoc Biol. 99:693–698. 2016. View Article : Google Scholar : PubMed/NCBI

18 

Wynn TA and Vannella KM: Macrophages in tissue repair, regeneration, and fibrosis. Immunity. 44:450–462. 2016. View Article : Google Scholar : PubMed/NCBI

19 

Beutler B: Microbe sensing, positive feedback loops, and the pathogenesis of inflammatory diseases. Immunol Rev. 227:248–263. 2009. View Article : Google Scholar : PubMed/NCBI

20 

Alexopoulou L, Holt AC, Medzhitov R and Flavell RA: Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature. 413:732–738. 2001. View Article : Google Scholar : PubMed/NCBI

21 

Ruiz J, Kanagavelu S, Flores C, Romero L, Riveron R, Shih DQ and Fukata M: Systemic activation of TLR3-dependent TRIF signaling confers host defense against gram-negative bacteria in the intestine. Front Cell Infect Microbiol. 5:1052016. View Article : Google Scholar : PubMed/NCBI

22 

Poltorak A, Smirnova I, Clisch R and Beutler B: Limits of a deletion spanning Tlr4 in C57BL/10ScCr mice. J Endotoxin Res. 6:51–56. 2000. View Article : Google Scholar : PubMed/NCBI

23 

Kagan JC and Medzhitov R: Phosphoinositide-mediated adaptor recruitment controls Toll-like receptor signaling. Cell. 125:943–955. 2006. View Article : Google Scholar : PubMed/NCBI

24 

Romieu-Mourez R, François M, Boivin MN, Bouchentouf M, Spaner DE and Galipeau J: Cytokine modulation of TLR expression and activation in mesenchymal stromal cells leads to a proinflammatory phenotype. J Immunol. 182:7963–7973. 2009. View Article : Google Scholar : PubMed/NCBI

25 

Xiong Y and Medvedev AE: Induction of endotoxin tolerance in vivo inhibits activation of IRAK4 and increases negative regulators IRAK-M, SHIP-1, and A20. J Leukoc Biol. 90:1141–1148. 2011. View Article : Google Scholar : PubMed/NCBI

26 

Xiong Y, Qiu F, Piao W, Song C, Wahl LM and Medvedev AE: Endotoxin tolerance impairs IL-1 receptor-associated kinase (IRAK) 4 and TGF-beta-activated kinase 1 activation, K63-linked polyubiquitination and assembly of IRAK1, TNF receptor-associated factor 6, and IkappaB kinase gamma and increases A20 expression. J Biol Chem. 286:7905–7916. 2011. View Article : Google Scholar : PubMed/NCBI

27 

Murphy MB, Xiong Y, Pattabiraman G, Manavalan TT, Qiu F and Medvedev AE: Pellino-3 promotes endotoxin tolerance and acts as a negative regulator of TLR2 and TLR4 signaling. J Leukoc Biol. 98:963–974. 2015. View Article : Google Scholar : PubMed/NCBI

28 

Foster SL, Hargreaves DC and Medzhitov R: Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature. 447:972–978. 2007.PubMed/NCBI

29 

O'Neill LA, Sheedy FJ and McCoy CE: MicroRNAs: The fine-tuners of Toll-like receptor signalling. Nat Rev Immunol. 11:163–175. 2011. View Article : Google Scholar : PubMed/NCBI

30 

Zhao W, Wang L, Zhang M, Wang P, Qi J, Zhang L and Gao C: Nuclear to cytoplasmic translocation of heterogeneous nuclear ribonucleoprotein U enhances TLR-induced proinflammatory cytokine production by stabilizing mRNAs in macrophages. J Immunol. 188:3179–3187. 2012. View Article : Google Scholar : PubMed/NCBI

31 

Zhang M, Wang L, Zhao X, Zhao K, Meng H, Zhao W and Gao C: TRAF-interacting protein (TRIP) negatively regulates IFN-β production and antiviral response by promoting proteasomal degradation of TANK-binding kinase 1. J Exp Med. 209:1703–1711. 2012. View Article : Google Scholar : PubMed/NCBI

32 

Chan ED and Riches DW: IFN-gamma + LPS induction of iNOS is modulated by ERK, JNK/SAPK, and p38(mapk) in a mouse macrophage cell line. Am J Physiol Cell Physiol. 280:C441–C450. 2001.PubMed/NCBI

33 

Kaminska B: MAPK signalling pathways as molecular targets for anti-inflammatory therapy–from molecular mechanisms to therapeutic benefits. Biochim Biophys Acta. 1754:253–262. 2005. View Article : Google Scholar : PubMed/NCBI

34 

Lee GL, Wu JY, Tsai CS, Lin CY, Tsai YT, Lin CS, Wang YF, Yet SF, Hsu YJ and Kuo CC: TLR4-activated MAPK-IL-6 axis regulates vascular smooth muscle cell function. Int J Mol Sci. 17:E13942016. View Article : Google Scholar : PubMed/NCBI

35 

Hu M, Fan M, Zhen J, Lin J, Wang Q, Lv Z and Wang R: FAK contributes to proteinuria in hypercholesterolaemic rats and modulates podocyte F-actin re-organization via activating p38 in response to ox-LDL. J Cell Mol Med. 21:552–567. 2017. View Article : Google Scholar

36 

Toledo FD, Basiglio CL, Barosso IR, Boaglio AC, Zucchetti AE, Sánchez Pozzi EJ and Roma MG: Mitogen-activated protein kinases are involved in hepatocanalicular dysfunction and cholestasis induced by oxidative stress. Arch Toxicol. 91:2391–2403. 2017. View Article : Google Scholar

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Copy and paste a formatted citation
Spandidos Publications style
Bian H, Li F, Wang W, Zhao Q, Gao S, Ma J, Li X, Ren W, Qin C, Qi J, Qi J, et al: MAPK/p38 regulation of cytoskeleton rearrangement accelerates induction of macrophage activation by TLR4, but not TLR3. Int J Mol Med 40: 1495-1503, 2017.
APA
Bian, H., Li, F., Wang, W., Zhao, Q., Gao, S., Ma, J. ... Qi, J. (2017). MAPK/p38 regulation of cytoskeleton rearrangement accelerates induction of macrophage activation by TLR4, but not TLR3. International Journal of Molecular Medicine, 40, 1495-1503. https://doi.org/10.3892/ijmm.2017.3143
MLA
Bian, H., Li, F., Wang, W., Zhao, Q., Gao, S., Ma, J., Li, X., Ren, W., Qin, C., Qi, J."MAPK/p38 regulation of cytoskeleton rearrangement accelerates induction of macrophage activation by TLR4, but not TLR3". International Journal of Molecular Medicine 40.5 (2017): 1495-1503.
Chicago
Bian, H., Li, F., Wang, W., Zhao, Q., Gao, S., Ma, J., Li, X., Ren, W., Qin, C., Qi, J."MAPK/p38 regulation of cytoskeleton rearrangement accelerates induction of macrophage activation by TLR4, but not TLR3". International Journal of Molecular Medicine 40, no. 5 (2017): 1495-1503. https://doi.org/10.3892/ijmm.2017.3143
Copy and paste a formatted citation
x
Spandidos Publications style
Bian H, Li F, Wang W, Zhao Q, Gao S, Ma J, Li X, Ren W, Qin C, Qi J, Qi J, et al: MAPK/p38 regulation of cytoskeleton rearrangement accelerates induction of macrophage activation by TLR4, but not TLR3. Int J Mol Med 40: 1495-1503, 2017.
APA
Bian, H., Li, F., Wang, W., Zhao, Q., Gao, S., Ma, J. ... Qi, J. (2017). MAPK/p38 regulation of cytoskeleton rearrangement accelerates induction of macrophage activation by TLR4, but not TLR3. International Journal of Molecular Medicine, 40, 1495-1503. https://doi.org/10.3892/ijmm.2017.3143
MLA
Bian, H., Li, F., Wang, W., Zhao, Q., Gao, S., Ma, J., Li, X., Ren, W., Qin, C., Qi, J."MAPK/p38 regulation of cytoskeleton rearrangement accelerates induction of macrophage activation by TLR4, but not TLR3". International Journal of Molecular Medicine 40.5 (2017): 1495-1503.
Chicago
Bian, H., Li, F., Wang, W., Zhao, Q., Gao, S., Ma, J., Li, X., Ren, W., Qin, C., Qi, J."MAPK/p38 regulation of cytoskeleton rearrangement accelerates induction of macrophage activation by TLR4, but not TLR3". International Journal of Molecular Medicine 40, no. 5 (2017): 1495-1503. https://doi.org/10.3892/ijmm.2017.3143
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