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Soy protein inhibits inflammation-induced VCAM-1 and inflammatory cytokine induction by inhibiting the NF-κB and AKT signaling pathway in apolipoprotein E–deficient mice

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Abstract

Purpose

Inflammation is a hallmark of many diseases, such as atherosclerosis, autoimmune diseases, obesity, and cancer. Isoflavone-free soy protein diet (SPI−) has been shown to reduce atherosclerotic lesions in a hyperlipidemic mouse model compared to casein (CAS)-fed mice, despite unchanged serum lipid levels. However, possible mechanisms contributing to the athero-protective effect of soy protein remain unknown. Therefore, we investigated whether and how SPI− diet inhibits inflammatory responses associated with atherosclerosis.

Methods

Apolipoprotein E knockout (apoE−/−) mice (5-week) were fed CAS or SPI− diet for 1 or 5 week to determine LPS- and hyperlipidemia-induced acute and chronic inflammatory responses, respectively. Expression of NF-κB-dependent inflammation mediators such as VCAM-1, TNF-α, and MCP-1 were determined in aorta and liver. NF-κB, MAP kinase, and AKT activation was determined to address mechanisms contributing to the anti-inflammatory properties of soy protein/peptides.

Results

Isoflavone-free soy protein diet significantly reduced LPS-induced VCAM-1 mRNA and protein expression in aorta compared to CAS-fed mice. Reduced VCAM-1 expression in SPI−-fed mice also paralleled attenuated monocyte adhesion to vascular endothelium, a critical and primary processes during inflammation. Notably, VCAM-1 mRNA and protein expression in lesion-prone aortic arch was significantly reduced in apoE−/− mice fed SPI− for 5 weeks compared with CAS-fed mice. Moreover, dietary SPI− potently inhibited LPS-induced NF-κB activation and the subsequent upregulation of pro-inflammatory cytokines, including TNF-α, IL-6, IL-1β, and MCP-1. Interestingly, SPI− inhibited NF-κB-dependent inflammatory responses by targeting I-κB phosphorylation and AKT activation with no effect on MAP kinase pathway. Of the five putative soy peptides, four of the soy peptides inhibited LPS-induced VCAM-1, IL-6, IL-8, and MCP-1 protein expression in human vascular endothelial cells in vitro.

Conclusions

Collectively, our findings suggest that anti-inflammatory properties of component(s) of soy protein/peptides may be a possible mechanism for the prevention of chronic inflammatory diseases such as atherosclerosis.

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Abbreviations

ApoE:

Apolipoprotein E

CAS:

Casein

ICAM-1:

Intercellular adhesion molecule-1

MCP-1:

Monocyte chemoattractant protein

PTEN:

Phosphatase and tensin homolog deleted on chromosome ten

SPI− :

Isoflavone-free soy protein isolate

TNF-α:

Tumor necrosis factor-α

VCAM-1:

Vascular cell adhesion molecule-1

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Acknowledgments

This work was supported by a grant from U.S. Department of Agriculture (CRIS-6251-51000-005-02S (SN) and SN was supported in part by intramural funds from the Experimental Pathology, Department of Pathology and Vascular Medicine Institute, University of Pittsburgh, PA. We thank John Gregan for his help with manuscript preparation. We also thank Van Goodwin III, Jessica Warden and Amy Greenway for technical assistance.

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

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Authors and Affiliations

  1. Arkansas Children’s Nutrition Center, Little Rock, AR, USA

    Ramona L. Burris & Shanmugam Nagarajan

  2. Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR, 72202, USA

    Hang-Pong Ng & Shanmugam Nagarajan

  3. Department of Pathology and Vascular Medicine Institute, University of Pittsburgh, BST E1256, 200 Lothrop Street, Pittsburgh, PA, 15261, USA

    Hang-Pong Ng & Shanmugam Nagarajan

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  1. Ramona L. Burris
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Correspondence to Shanmugam Nagarajan.

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Burris, R.L., Ng, HP. & Nagarajan, S. Soy protein inhibits inflammation-induced VCAM-1 and inflammatory cytokine induction by inhibiting the NF-κB and AKT signaling pathway in apolipoprotein E–deficient mice. Eur J Nutr 53, 135–148 (2014). https://doi.org/10.1007/s00394-013-0509-7

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