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Role of Leptin and SOCS3 in Inhibiting the Type I Interferon Response During Obesity

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Abstract

Obesity provokes an imbalance in the immune system, including an aberrant type I interferon response during some viral infections and after TLR stimulation. SOCS3 overexpression and altered systemic leptin levels could be responsible for the reduced type I interferon production in people with obesity and, eventually, significantly increase the risk of viral infection. The aim of this study was to determine whether SOCS3- and leptin-induced tolerance are responsible for the reduced type I interferon production in people with obesity. SOCS3 overexpression in PBMCs from people with obesity was inhibited with the small interfering RNA (siRNA) assay, and leptin-induced tolerance was evaluated in PBMCs from non-obese volunte\ers and U937 cells treated with TLR ligands. SOCS3, but not SOCS1, gene silencing via siRNA increased the type I interferon response in PBMCs obtained from people with obesity. On the other hand, leptin induced SOCS3 expression and inhibited type I interferons in PBMCs from healthy donors and in U937 monocytes stimulated with TLR ligands. Taken together, these results demonstrate that reduced type I interferon production in obesity is caused by SOCS3 overexpression as well as tolerance induced by leptin. Here, we demonstrate a key role of leptin and SOCS3 in inhibiting the type I interferon response during obesity.

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References

  1. Kanneganti, T.D., and V.D. Dixit. 2012. Immunological complications of obesity. Nature Immunology 13: 707–12.

    Article  CAS  PubMed  Google Scholar 

  2. Ouchi, N., J.L. Parker, J.J. Lugus, and K. Walsh. 2011. Adipokines in inflammation and metabolic disease. Nature Reviews Immunology 11: 85–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lago, F., C. Dieguez, J. Gómez-Reino, and O. Gualillo. 2007. Adipokines as emerging mediators of immune response and inflammation. Nature Clinical Practice Rheumatology 3: 716–24.

    Article  CAS  PubMed  Google Scholar 

  4. Maffei, M., J. Halaas, E. Ravussin, R. Pratley, G. Lee, Y. Zhang, et al. 1995. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nature Medicine 1: 1155–61.

    Article  CAS  PubMed  Google Scholar 

  5. Zarkesh-Esfahani, H., A.G. Pockley, Z. Wu, P.G. Hellewell, A.P. Weetman, and R.J. Ross. 2004. Leptin indirectly activates human neutrophils via induction of TNF-α. The Journal of Immunology 172: 1809–14.

    Article  CAS  PubMed  Google Scholar 

  6. Zarkesh-Esfahani, H., G. Pockley, R.A. Metcalfe, M. Bidlingmaier, Z. Wu, A. Ajami, et al. 2001. High-dose leptin activates human leukocytes via receptor expression on monocytes. The Journal of Immunology 167: 4593–9.

    Article  CAS  PubMed  Google Scholar 

  7. Lord, G.M., G. Matarese, J.K. Howard, R.J. Baker, S.R. Bloom, and R.I. Lechler. 1998. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 394: 897–901.

    Article  CAS  PubMed  Google Scholar 

  8. Myers, M.G., M.A. Cowley, and H. Münzberg. 2008. Mechanisms of leptin action and leptin resistance. Annual Review of Physiology 70: 537–56.

    Article  CAS  PubMed  Google Scholar 

  9. Bjørbæk, C., J.K. Elmquist, J.D. Frantz, S.E. Shoelson, and J.S. Flier. 1998. Identification of SOCS-3 as a potential mediator of central leptin resistance. Molecular Cell 1: 619–25.

    Article  PubMed  Google Scholar 

  10. Rui, L., M. Yuan, D. Frantz, S. Shoelson, and M.F. White. 2002. SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. Journal of Biological Chemistry 277: 42394–8.

    Article  CAS  PubMed  Google Scholar 

  11. Teran-Cabanillas, E., M. Montalvo-Corral, G. Caire-Juvera, S.Y. Moya-Camarena, and J. Hernández. 2013. Decreased interferon-α and interferon-β production in obesity and expression of suppressor of cytokine signaling. Nutrition 29: 207–12.

    Article  CAS  PubMed  Google Scholar 

  12. Ahmad, R., A. Al-Mass, V. Atizado, A. Al-Hubail, F. Al-Ghimlas, M. Al-Arouj, et al. 2012. Elevated expression of the toll like receptors 2 and 4 in obese individuals: its significance for obesity-induced inflammation. Journal of inflammation (Lond, England) 9: 48.

    Article  CAS  Google Scholar 

  13. Dasu, M.R., S. Devaraj, S. Park, and I. Jialal. 2010. Increased toll-like receptor (TLR) activation and TLR ligands in recently diagnosed type 2 diabetic subjects. Diabetes Care 33: 861–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Dasu, M.R., S. Devaraj, L. Zhao, D.H. Hwang, and I. Jialal. 2008. High glucose induces toll-like receptor expression in human monocytes mechanism of activation. Diabetes 57: 3090–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yang Y, Sun H, Mo X, Liu Y, Jia H, Li X, et al. Prediction of novel genes associated with negative regulators of toll-like receptors-induced inflammation based on endotoxin tolerance. Inflammation. 2012:1–11

  16. de Vos, A.F., J.M. Pater, P.S. van den Pangaart, M.D. de Kruif, C. van’t Veer, and T. van der Poll. 2009. In vivo lipopolysaccharide exposure of human blood leukocytes induces cross-tolerance to multiple TLR ligands. The Journal of Immunology 183: 533–42.

    Article  PubMed  Google Scholar 

  17. Walsh, M., J. Jonsson, M.M. Richardson, G. Lipka, D. Purdie, A. Clouston, et al. 2006. Non-response to antiviral therapy is associated with obesity and increased hepatic expression of suppressor of cytokine signalling 3 (SOCS-3) in patients with chronic hepatitis C, viral genotype 1. Gut 55: 529.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ueki, K., T. Kondo, and C.R. Kahn. 2004. Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Molecular and Cellular Biology 24: 5434–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yang, Z., M. Hulver, R.P. McMillan, L. Cai, E.E. Kershaw, L. Yu, et al. 2012. Regulation of insulin and leptin signaling by muscle suppressor of cytokine signaling 3 (SOCS3). PloS One 7: e47493.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Van Heek, M., D.S. Compton, C.F. France, R.P. Tedesco, A.B. Fawzi, M.P. Graziano, et al. 1997. Diet-induced obese mice develop peripheral, but not central, resistance to leptin. The Journal of Clinical Investigation 99: 385–90.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Baetz, A., M. Frey, K. Heeg, and A.H. Dalpke. 2004. Suppressor of cytokine signaling (SOCS) proteins indirectly regulate toll-like receptor signaling in innate immune cells. Journal of Biological Chemistry 279: 54708–15.

    Article  CAS  PubMed  Google Scholar 

  22. Wunderlich, C.M., N. Hövelmeyer, and F.T. Wunderlich. 2013. Mechanisms of chronic JAK-STAT3-SOCS3 signaling in obesity. JAK-STAT. 2: e23878.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Loseke, S., E. Grage-Griebenow, A. Wagner, K. Gehlhar, and A. Bufe. 2003. Differential expression of IFN-[alpha] subtypes in human PBMC: evaluation of novel real-time PCR assays. Journal of Immunological Methods 276: 207–22.

    Article  CAS  PubMed  Google Scholar 

  24. Jia, D., R. Rahbar, R.W.Y. Chan, S.M.Y. Lee, M.C.W. Chan, B.X. Wang, et al. 2010. Influenza virus non-structural protein 1 (NS1) disrupts interferon signaling. PloS One 5: e13927.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Terán-Cabanillas E, Montalvo-Corral M, Silva-Campa E, Caire-Juvera G, Moya-Camarena SY, Hernández J. Production of interferon α and β, pro-inflammatory cytokines and the expression of suppressor of cytokine signaling (SOCS) in obese subjects infected with influenza A/H1N1. Clinical nutrition (Edinburgh, Scotland). 2014;33:922–6.

  26. Michaud, F., F. Coulombe, E. Gaudreault, C. Paquet-Bouchard, M. Rola-Pleszczynski, and J. Gosselin. 2010. Epstein-Barr virus interferes with the amplification of IFNalpha secretion by activating suppressor of cytokine signaling 3 in primary human monocytes. PloS One 5: e11908.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Pauli, E.K., M. Schmolke, T. Wolff, D. Viemann, J. Roth, J.G. Bode, et al. 2008. Influenza A virus inhibits type I IFN signaling via NF-kB-dependent induction of SOCS-3 expression. PLoS Pathogens 4: e1000196.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Vlotides, G., A.S. Sörensen, F. Kopp, K. Zitzmann, N. Cengic, S. Brand, et al. 2004. SOCS-1 and SOCS-3 inhibit IFN-[alpha]-induced expression of the antiviral proteins 2, 5-OAS and MxA. Biochemical and Biophysical Research Communications 320: 1007–14.

    Article  CAS  PubMed  Google Scholar 

  29. Papathanassoglou, E., K. El-Haschimi, X.C. Li, G. Matarese, T. Strom, and C. Mantzoros. 2006. Leptin receptor expression and signaling in lymphocytes: kinetics during lymphocyte activation, role in lymphocyte survival, and response to high fat diet in mice. The Journal of Immunology 176: 7745–52.

    Article  CAS  PubMed  Google Scholar 

  30. Smith, A.G., P.A. Sheridan, J.B. Harp, and M.A. Beck. 2007. Diet-induced obese mice have increased mortality and altered immune responses when infected with influenza virus. The Journal of Nutrition 137: 1236–43.

    CAS  PubMed  Google Scholar 

  31. Jaedicke, K.M., A. Roythorne, K. Padget, S. Todryk, P.M. Preshaw, and J.J. Taylor. 2013. Leptin up-regulates TLR2 in human monocytes. Journal of Leukocyte Biology.

  32. Loffreda, S., S. Yang, H. Lin, C. Karp, M. Brengman, D. Wang, et al. 1998. Leptin regulates proinflammatory immune responses. The FASEB Journal 12: 57–65.

    CAS  PubMed  Google Scholar 

  33. Santos-Alvarez, J., R. Goberna, and V. Sánchez-Margalet. 1999. Human leptin stimulates proliferation and activation of human circulating monocytes. Cellular Immunology 194: 6–11.

    Article  CAS  PubMed  Google Scholar 

  34. Cantaert, T., D. Baeten, P.P. Tak, and L.G. van Baarsen. 2010. Type I IFN and TNFα cross-regulation in immune-mediated inflammatory disease: basic concepts and clinical relevance. Arthritis Research and Therapy 12: 219.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Ivashkiv, L.B. 2003. Type I, interferon modulation of cellular responses to cytokines and infectious pathogens: potential role in SLE pathogenesis. Autoimmunity 36: 473–9.

    Article  CAS  PubMed  Google Scholar 

  36. Palucka, A.K., J.-P. Blanck, L. Bennett, V. Pascual, and J. Banchereau. 2005. Cross-regulation of TNF and IFN-α in autoimmune diseases. Proceedings of the National Academy of Sciences of the United States of America 102: 3372–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This study was partially supported by the FONDO SECTORIAL SALUD-CONACYT grant no. 127013. We thank Monica Resendiz for her technical assistance. We thank the volunteers for their participation.

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Author notes

  1. Elí Terán-Cabanillas

    Present address: Unidad Académica de Ciencias de la Nutrición y Gastronomía, Universidad Autónoma de Sinaloa, Sinaloa, México

Authors and Affiliations

  1. Laboratorio de Inmuología, Coordinación de Nutrición, Centro de Investigación en Alimentación y Desarrollo, A.C., Km 0.6 Carretera a la Victoria, Hermosillo, Sonora, México, 83000

    Elí Terán-Cabanillas & Jesús Hernández

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  1. Elí Terán-Cabanillas
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  2. Jesús Hernández
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Correspondence to Jesús Hernández.

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Terán-Cabanillas, E., Hernández, J. Role of Leptin and SOCS3 in Inhibiting the Type I Interferon Response During Obesity. Inflammation 40, 58–67 (2017). https://doi.org/10.1007/s10753-016-0452-x

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