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Sodium Fluoride (NaF) Induces Inflammatory Responses Via Activating MAPKs/NF-κB Signaling Pathway and Reducing Anti-inflammatory Cytokine Expression in the Mouse Liver

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Abstract

At present, no reports are focused on fluoride-induced hepatic inflammatory responses in human beings and animals. This study aimed to investigate the mRNA and protein levels of inflammatory cytokines and signaling molecules for evaluating the effect of different doses (0, 12, 24, and 48 mg/kg) of sodium fluoride (NaF) on inflammatory reaction in the mouse liver by using methods of experimental pathology, quantitative real-time polymerase chain reaction (qRT-PCR), and western blot analysis. We found that NaF in excess of 12 mg/kg caused the hepatic inflammatory responses, and the results showed that NaF activated the mitogen-activated protein kinases (MAPKs) signaling pathway by markedly increasing (p < 0.01 or p < 0.05) mRNA and protein levels of apoptosis signal-regulating kinase 1 (ASK1), mitogen-activated protein kinase kinases 1/2 (MEK1/2), extracellular signal-regulated protein kinases 1/2 (Erk1/2), mitogen-activated protein kinase kinases 4/7 (MEK4/7), c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38) and mitogen-activated protein kinase kinases 3/6 (MEK3/6), and the nuclear factor-kappa B (NF-κB) signaling pathway by increasing (p < 0.01 or p < 0.05) the production of NF-κB and inhibitor of nuclear factor kappa-B kinase subunit beta (IKK-β) and reducing (p < 0.01 or p < 0.05) the production of the inhibitory kappa B (IκB). Thus, NaF that caused the hepatic inflammatory responses was characterized by increasing (p < 0.01 or p < 0.05) the production of pro-inflammatory mediators such as interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), monocyte chemotactic protein 1 (MCP-1), and cyclooxygenase-2 (COX-2) via the activation of MAPKs and NF-κB pathways, and by significantly inhibiting (p < 0.01 or p < 0.05) the production of anti-inflammatory mediators including interleukin-4 (IL-4) and transforming growth factor beta (TGF-β).

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Abbreviations

NaF:

Sodium fluoride

qRT-PCR:

Quantitative real-time polymerase chain reaction

MAPKs:

Mitogen-activated protein kinases

ASK1:

Apoptosis signal-regulating kinase 1

MEK1/2:

Mitogen-activated protein kinase kinases 1/2

Erk1/2:

Extracellular signal-regulated protein kinases 1/2

MEK4/7:

Mitogen-activated protein kinase kinases 4/7

JNK:

c-Jun N-terminal kinase

MEK3/6:

Mitogen-activated protein kinase kinases 3/6

p38:

p38 mitogen-activated protein kinase

NF-κB:

Nuclear factor-kappa B

IKK-β:

Nuclear factor kappa-B kinase subunit beta

IκB:

Inhibitory kappa B

IL-1β:

Interleukin-1β

IL-6:

Interleukin-6

IL-8:

Interleukin-8

MCP-1:

Monocyte chemotactic protein 1

COX-2:

Cyclooxygenase-2

IL-4:

Interleukin-4

TGF-β:

Transforming growth factor beta

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Acknowledgments

The study was supported by the program for Changjiang scholars and innovative research team in university (IRT 0848) and the Shuangzhi Project of Sichuan Agricultural University (03572437; 03573050).

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Author notes

  1. Linlin Chen, Ping Kuang and Huan Liu contributed equally to this work.

Authors and Affiliations

  1. College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu, 611130, China

    Linlin Chen, Ping Kuang, Huan Liu, Qin Wei, Hengmin Cui, Jing Fang, Zhicai Zuo, Junliang Deng, Yinglun Li, Xun Wang & Ling Zhao

  2. Key Laboratory of Animal Diseases and Environmental Hazards of Sichuan Province, Sichuan Agriculture University, Wenjiang, Chengdu, 611130, China

    Hengmin Cui, Jing Fang, Zhicai Zuo, Junliang Deng, Yinglun Li, Xun Wang & Ling Zhao

  3. Key Laboratory of Agricultural Information Engineering of Sichuan Province, Sichuan Agriculture University, Ya’an, 625014, Sichuan, China

    Hengmin Cui

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Contributions

L. Chen, P. Kuang, and H. Cui designed the experiments. L. Chen, P. Kuang, H. Liu, and Q. Wei carried out the experiments. L. Chen, P. Kuang, H. Liu, Q. Wei, J. Fang, Z. Zuo, J. Deng., Y. Li, X. Wang, and L. Zhao analyzed and interpreted data. L. Chen, P. Kuang, H. Liu, and H. Cui wrote and revised the manuscript.

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Correspondence to Hengmin Cui.

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Chen, L., Kuang, P., Liu, H. et al. Sodium Fluoride (NaF) Induces Inflammatory Responses Via Activating MAPKs/NF-κB Signaling Pathway and Reducing Anti-inflammatory Cytokine Expression in the Mouse Liver. Biol Trace Elem Res 189, 157–171 (2019). https://doi.org/10.1007/s12011-018-1458-z

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