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Roles of Toll-Like Receptor 4, IκB Kinase, and the Proteasome in the Intestinal Alterations Caused by Sepsis

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Abstract

Background

Lipopolysaccharide decreases intestinal contractility and induces the production of cytokines, which play an important role in the pathogenesis of sepsis.

Aim

The objective of the present study was to examine the role of Toll-like receptor 4, IκB kinase, and the proteasome in the intestinal alterations induced by lipopolysaccharide.

Methods

Sepsis was induced in rabbits by intravenous injection of lipopolysaccharide. Contractility studies of rabbit duodenum were performed in an organ bath. Expressions of interleukin-1β, interleukin-6, interleukin-8, interleukin-10, IκB kinase-α, IκB kinase-β, IκB kinase-γ, and the proteasome mRNA were determined by RT-PCR on rabbit duodenum.

Results

Neomycin and polymyxin B (Toll-like receptor 4 inhibitors), IKK NBD peptide (IκB kinase complex inhibitor), and MG-132 (proteasome inhibitor) blocked partially the effects of lipopolysaccharide on the acetylcholine-, prostaglandin E2-, substance P-, and KCl-induced contractions in the longitudinal and circular smooth muscle of rabbit duodenum. Lipopolysaccharide increased the mRNA expression of interleukin-6 and interleukin-8 in duodenal tissue, and this effect was partly reversed by neomycin, polymyxin B, IKK NBD peptide, and MG-132. IκB kinase-α, IκB kinase-β, IκB kinase-γ, and the proteasome mRNA expressions was not affected by lipopolysaccharide treatment.

Conclusions

Toll-like receptor 4, the IκB kinase complex, and the proteasome could be therapeutic targets in the treatment of sepsis symptoms in the intestine.

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Acknowledgments

This work was funded by Gobierno de Aragón (B61/2013), Spain.

Conflict of interest

None.

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Authors and Affiliations

  1. Department of Pharmacology and Physiology, Faculty of Veterinary Medicine, University of Zaragoza, c/ Miguel Servet 177, 50013, Saragossa, Spain

    Sergio Gonzalo, Marta Sofía Valero, Fernando Martínez de Salinas, Claudia Vergara, María Pilar Arruebo, Miguel Ángel Plaza, María Divina Murillo & Laura Grasa

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  1. Sergio Gonzalo
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  2. Marta Sofía Valero
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  3. Fernando Martínez de Salinas
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  4. Claudia Vergara
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  5. María Pilar Arruebo
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  6. Miguel Ángel Plaza
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  7. María Divina Murillo
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  8. Laura Grasa
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Corresponding author

Correspondence to Laura Grasa.

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Gonzalo, S., Valero, M.S., Martínez de Salinas, F. et al. Roles of Toll-Like Receptor 4, IκB Kinase, and the Proteasome in the Intestinal Alterations Caused by Sepsis. Dig Dis Sci 60, 1223–1231 (2015). https://doi.org/10.1007/s10620-014-3418-6

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  • DOI: https://doi.org/10.1007/s10620-014-3418-6

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