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Plasminogen Activator Inhibitor-1 Regulates LPS-Induced TLR4/MD-2 Pathway Activation and Inflammation in Alveolar Macrophages

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Abstract

Toll-like receptor 4 (TLR4) and myeloid differentiation protein 2 (MD-2) are the main lipopolysaccharide (LPS) binding receptors that respond to inflammatory stimuli and mediate NF-kappa B (NF-κB) signaling pathway in macrophages. We have previously shown that plasminogen activator inhibitor-1 (PAI-1) deletion increased lung injury induced by intratracheal instillation of LPS through downregulation of TLR4 negative regulators. However, the mechanisms by which PAI-1 regulates lung inflammation are largely unknown. The aim of this study is to assess the relationship between PAI-1 and TLR4 signaling pathways in LPS-induced NR8383 cells inflammatory reaction. The results showed that the levels of PAI-1, TNF-α, and IL-1β protein were increased remarkably in NR8383 cell supernatants after LPS stimulation. PAI-1 gene knockdown reduced TNF-α and IL-1β levels in cell supernatants and inhibited the NF-κB p65 protein expression in NR8383 cells. The upregulated mRNA and protein expressions of TLR4, MD-2, and myeloid differentiation protein (MyD88) induced by LPS were attenuated after PAI-1 gene knockdown. Conversely, overexpression of PAI-1 in NR8383 cells not only resulted in additional mRNA and protein production of PAI-1, TLR4, MD-2, and MyD88, it also aggravated the inflammatory response induced by LPS. In conclusion, PAI-1 contributes to the regulation of LPS-induced inflammatory response in NR8383 cells, likely by affecting the TLR4-MD-2/NF-κB signaling transduction pathway.

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Abbreviations

LPS:

Lipopolysaccharide

PAI-1:

Plasminogen activator inhibitor-1

TLR4:

Toll-like receptor 4

MD-2:

Myeloid differentiation protein 2

MyD88:

Myeloid differentiation protein

IRAK-M:

Interleukin-1 receptor associated kinase M

NF-κB:

Nuclear factor (NF)-kappa B

AMs:

Alveolar macrophages

ALI:

Acute lung injury

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ACKNOWLEDGMENTS

This work was financially supported by the Nature Science Foundation of Shanghai Science Committee (12ZR1405100) and National Natural Science Fund project (81300054, 81270137).

Conflict of Interest

There are no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Geriatrics, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China

    Weiying Ren

  2. Department of Pulmonary Medicine, Research Institute of Respiratory Disease, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China

    Weiying Ren, Zhonghui Wang & Lei Zhu

  3. Department of Respiratory Medicine, Huzhou Central Hospital, Zhejiang, China

    Feng Hua

Authors
  1. Weiying Ren
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  2. Zhonghui Wang
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  4. Lei Zhu
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Correspondence to Lei Zhu.

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Ren, W., Wang, Z., Hua, F. et al. Plasminogen Activator Inhibitor-1 Regulates LPS-Induced TLR4/MD-2 Pathway Activation and Inflammation in Alveolar Macrophages. Inflammation 38, 384–393 (2015). https://doi.org/10.1007/s10753-014-0042-8

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  • DOI: https://doi.org/10.1007/s10753-014-0042-8

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