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Modulatory Effect of Whey Proteins in Some Cytokines Involved in Wound Healing in Male Diabetic Albino Rats

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Abstract

The anti-inflammatory cytokines (interleukin (IL)-4 and IL-10) and the pro-inflammatory cytokines (IL-1β, IL-6, and tumor necroses factor-alpha (TNF-α)) have important functions in wound healing. Thus, the aim of this study was to determine whether dietary supplementation with whey protein could enhance normal inflammatory responses during wound healing in diabetic rats. In this study, male albino rats were divided into a wounded control group, a wounded diabetic group, and a wounded diabetic group supplemented with whey protein orally at a dose of 100 mg/kg body weight. Tested rats showed increasing wound closure in rats treated with whey protein. In addition, after 4 days of wound, modulation in IL-4, IL-10, IL-1β, IL-6, and TNF-α levels were detected. Statistical analysis of data showed significant difference between the whey-protein-treated group and either control or diabetic groups (P < 0.05). Dietary supplementation with whey protein enhances the normal inflammatory responses during wound healing in diabetic rats by modulating the levels of some anti-inflammatory and inflammatory cytokines.

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References

  1. Werner, S., and R. Grose. 2003. Regulation of wound healing by growth factors and cytokines. Physiological Reviews 83: 835–870.

    PubMed  CAS  Google Scholar 

  2. Mercado, A.M., N. Quan, D.A. Padgett, J.F. Sheridan, and P.T. Marucha. 2002. Restraint stress alters the expression of interleukin-1 and keratinocyte growth factor at the wound site: an in situ hybridization study. Journal of Neuroimmunology 129: 74–83.

    Article  PubMed  CAS  Google Scholar 

  3. Singer, A.J., and R.A. Clark. 1999. Cutaneous wound healing. New England Journal of Medicine 341: 738–746.

    Article  PubMed  CAS  Google Scholar 

  4. Delgado, A.V., A.T. McManus, and J.P. Chambers. 2003. Production of tumor necrosis factor-alpha, interleukin 1-beta, interleukin 2, and interleukin 6 by rat leukocyte subpopulations after exposure to substance P. Neuropeptides 37: 355–361.

    Article  PubMed  CAS  Google Scholar 

  5. Molloy, T., Y. Wang, and G. Murrell. 2003. The roles of growth factors in tendon and ligament healing. Sports Medicine 33: 381–394.

    Article  PubMed  Google Scholar 

  6. Vegesna, V., W.H. McBride, J.M. Taylor, and H.R. Withers. 1995. The effect of interleukin-1 beta or transforming growth factor-beta on radiation-impaired murine skin woundhealing. Journal of Surgical Research 59: 699–704.

    Article  PubMed  CAS  Google Scholar 

  7. Anjana, G., K. Sandeep, K. Dilip, and K.B. Ashok. 2010. Wound healing potential of Ocimum sanctum Linn. With induction of tumor necrosis factor-α. Indian Journal of Experimental Biology 48: 402–406.

    Google Scholar 

  8. Molly, M.M., M.F. Holly, M.Z. Paluch, Vummidi Giridhar Premkumar, Carol A. Mercer, Sara C. Kozma, and F.D. Angela. 2010. Differences in wound healing in mice with deficiency of IL-6 versus IL-6 receptor. Journal of Immunol 184: 7219–7228.

    Article  Google Scholar 

  9. Kondo, T., and T. Ohshima. 1996. The dynamics of inflammatory cytokines in the healing process of mouse skin wound: a preliminary study for possible wound age determination. International Journal of Legal Medicine 108: 231–236.

    Article  PubMed  CAS  Google Scholar 

  10. Paquet, P., and G.E. Pierard. 1996. Interleukin-6 and the skin. International Archives of Allergy and Immunology 109: 308–317.

    Article  PubMed  CAS  Google Scholar 

  11. Sawamura, D., X. Meng, S. Ina, M. Sato, K. Tamai, K. Hanada, and I. Hashimoto. 1998. Induction of keratinocyte proliferation and lymphocytic infiltration by in vivo introduction of the IL-6 gene into keratinocytes and possibility of keratinocyte gene therapy for inflammatory skin diseases using IL-6 mutant genes. Journal of Immunology 161: 5633–5639.

    CAS  Google Scholar 

  12. Turksen, K., T. Kupper, L. Degenstein, I. Williams, and E. Fuchs. 1992. Interleukin 6: insights to its function in skin by overexpression in transgenic mice. Proceedings of the National Academy of Sciences of the United States of America 89: 5068–5072.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  13. Peyron, E., and J. Banchereau. 1994. Interleukin-4: Structure, function, and clinical aspects. European Journal of Dermatology 4: 181–188.

    CAS  Google Scholar 

  14. Gillery, P., C. Fertin, J.F. Nicolas, F. Chastang, B. Kalis, J. Banchereau, and F.X. Maquart. 1992. Interleukin-4 stimulates collagen gene expression in human fibroblast monolayer cultures. Potential role in fibrosis. FEBS Letters 302: 231–234.

    Article  PubMed  CAS  Google Scholar 

  15. Ve´ronique, S., R. Laurent, G. Gaston, B. Philippe, G. Moncef, B. Philippe, and M. Francois-Xavier. 2000. Implication of interleukin-4 in wound healing. Laboratory Investigation 80: 1337–1343.

    Article  Google Scholar 

  16. Moore, K.W., R. de Waal Malefytq, R.L. Coffman, and A. O’Garra. 2001. Interleukin-10 and the interleukin-10 receptor. Annual Review of Immunology 19: 683–765.

    Article  PubMed  CAS  Google Scholar 

  17. Sato, Y., T. Ohshima, and T. Kondo. 1999. Regulatory role of endogenous interleukin-10 in cutaneous inflammatory response of murine wound healing. Biochemical and Biophysical Research Communications 265: 194–199.

    Article  PubMed  CAS  Google Scholar 

  18. Moore, K.W., A. O’Garra, R. de Waal Malefyt, P. Vieira, and T.R. Mosmann. 1993. Interleukin-10. Annual Review of Immunology 11: 165–190.

    Article  PubMed  CAS  Google Scholar 

  19. Engelhardt, E., A. Toksoy, M. Goebeler, S. Debus, E.B. Brocker, and R. Gillitzer. 1998. Chemokines IL-8, GROalpha, MCP-1, IP-10, and Mig are sequentially and differentially expressed during phase-specific infiltration of leukocyte subsets in human wound healing. American Journal of Pathology 153: 1849–1860.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Pari, L., and P. Murugan. 2007. Tetrahydrocurcumin prevents brain lipid peroxidation in streptozotocin-induced diabetic rats. Journal of Medicinal Food 10: 323–329.

    Article  PubMed  CAS  Google Scholar 

  21. Zi-Qing, L., K. Toshikazu, I. Yuko, T. Tatsunori, and M. Naofumi. 2003. Essential involvement of IL-6 in the skin wound-healing process as evidenced by delayed wound healing in IL-6-deficient mice. Journal of Leukocyte Biology 73: 713–721.

    Article  Google Scholar 

  22. Zhang, X., M. Kohli, Q. Zhou, D.T. Graves, and S. Amar. 2004. Short and long-term effects of IL-1 and TNF antagonists on periodontal wound healing. Journal of Immunology 173: 3514–3523.

    Article  CAS  Google Scholar 

  23. Dinarello, C.A. 1993. Modalities for reducing interleukin-1 activity in disease. Immunology Today 14: 155–159.

    Article  CAS  Google Scholar 

  24. Narayanan, S., A. Glasser, Y.S. Hu, and A.M. McDermott. 2005. The effectof interleukin-1 on cytokine gene expression by human corneal epithelial cells. Experimental Eye Research 80: 175–183.

    Article  PubMed  CAS  Google Scholar 

  25. Takami, Y., T. Motoki, I. Yamamoto, and E. Gohda. 2005. Synergistic induction of hepatocyte growth factor in human skin fibroblasts by the inflammatory cytokines interleukin-1 and interferon-gamma. Biochemical and Biophysical Research Communications 327: 212–217.

    Article  PubMed  CAS  Google Scholar 

  26. Dasu, M.R., R.E. Barrow, M. Spies, and D.N. Herndon. 2003. Matrix metalloproteinase expression in cytokine stimulated human dermal fibroblasts. Burns 29: 527–531.

    Article  PubMed  Google Scholar 

  27. Kopf, M., H. Baumann, G. Freer, M. Freudenberg, M. Lamers, T. Kishimoto, R. Zinkernagel, H. Bluethmann, and G. Kohler. 1994. Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature 368: 339–342.

    Article  PubMed  CAS  Google Scholar 

  28. Sato, Y., and T. Ohshima. 2000. The expression of mRNA of proinflammatory cytokines during skin wound healing in mice: a preliminary study for forensic wound age estimation (II). International Journal of Legal Medicine 113: 140–145.

    Article  PubMed  CAS  Google Scholar 

  29. Gallucci, R.M., P.P. Simeonova, J.M. Matheson, C. Kommineni, J.L. Guriel, T. Sugawara, and M.I. Luster. 2000. Impaired cutaneous wound healing in interleukin-6-deficient and immunosuppressed mice. FASEB Journal 14: 2525–2531.

    Article  PubMed  CAS  Google Scholar 

  30. Natsume, M., H. Tsuji, A. Harada, M. Akiyama, T. Yano, H. Ishikura, I. Nakanishi, K. Matsushima, S. Kaneko, and N. Mukaida. 1999. Attenuated liver fibrosis and depressed serum albumin levels in carbon tetrachloridetreated IL-6-deficient mice. Journal of Leukocyte Biology 66: 601–608.

    PubMed  CAS  Google Scholar 

  31. Greenwel, P., J. Rubin, M. Schwartz, E.L. Hertzberg, and M. Rojkind. 1993. Liver fat-storing cell clones obtained from a CCl4-cirrhotic rat are heterogeneous with regard to proliferation, expression of extracellular matrix components, interleukin-6, and connexin 43. Laboratory Investigation 69: 210–216.

    PubMed  CAS  Google Scholar 

  32. Yunsook, L., A.L. Mark, M. Tammy, and Bray. 2006. Dietary supplementation of N-acetylcysteine enhances early inflammatory responses during cutaneous wound healing in protein malnourished mice. Journal of Nutritional Biochemistry 17: 328–336.

    Article  Google Scholar 

  33. Frank, S., G. Hubner, G. Breier, M.T. Longaker, D.G. Greenhalgh, and S. Werner. 1995. Regulation of vascular endothelial growth factor expression in cultured keratinocytes. Implications for normal and impaired wound healing. Journal of Biological Chemistry 270: 12607–12613.

    Article  PubMed  CAS  Google Scholar 

  34. Bickel, M., S.M. Nothen, K. Freiburghaus, and D. Shire. 1996. Chemokine expression in human oral keratinocyte cell lines and keratinized mucosa. Journal of Dental Research 75: 1827–1834.

    Article  PubMed  CAS  Google Scholar 

  35. Nian, M., P. Lee, N. Khaper, and P. Liu. 2004. Inflammatory cytokines and postmyocardial infarction remodeling. Circulation Research 94: 1543–1553.

    Article  PubMed  CAS  Google Scholar 

  36. Serpier, H., P. Gillery, V. Salmon-Her, R. Garnotel, N. Georges, B. Kalis, and F.X. Maquart. 1997. Antagonistic effects of interferon-g and interleukin-4 on fibroblast cultures. Journal of Investigative Dermatology 109: 158–162.

    Article  PubMed  CAS  Google Scholar 

  37. Kucukcelebi, A., R.H.C. Harries, P.J. Hennessey, L.G. Phillips, L.D. Broemeling, D. Listengarten, F. Ko, S. Narula, and M.C. Robson. 1995. In vivo characterization of interleukin-4 as a potential wound healing agent. Wound Repair and Regeneration 3: 49–58.

    Article  PubMed  CAS  Google Scholar 

  38. Leonardi, A., R. Cortivo, I. Fregona, M. Plebani, A.G. Secchi, and G. Abatangelo. 2003. Effects of Th2 cytokines on expression of collagen, MMP-1, and TIMP-1 in conjunctival fibroblasts. Investigative Ophthalmology and Vision Science 44: 183–189.

    Article  Google Scholar 

  39. Sabine, A., S.W. Eming, B. Philippe, W. Claudia, S. Lisa, U. Olaf, M. Jeffrey, T.K. Davidson, and R. Axel. 2007. Accelerated Wound Closure in Mice Deficient for Interleukin-10. American Journal of Pathology 170: 188–202.

    Article  Google Scholar 

  40. Liechty, K.W., N.S. Adzick, and T.M. Crombleholme. 2000. Diminished interleukin 6 (IL-6) production during scarless human fetal wound repair. Cytokine 12: 671–676.

    Article  PubMed  CAS  Google Scholar 

  41. Gamal, B. 2012. Supplementation with undenatured whey protein during diabetes mellitus improves the healing and closure of diabetic wounds through the rescue of functional long-lived wound macrophages. Cellular Physiology and Biochemistry 29: 571–582.

    Article  Google Scholar 

  42. Gamal, B., M.B. Badr, H.M. Mohamed, M. Mohamed, M.R. Danny, and G. Olivier. 2012. Treatment of diabetic mice with undenatured whey protein accelerates the wound healing process by enhancing the expression of MIP-1α, MIP-2, KC, CX3CL1 and TGF-β in wounded tissue. BMC Immunology 13: 32.

    Article  Google Scholar 

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Acknowledgments

I thank Prof. Dr. Mohamed H.I. (Zoology Department, Faculty of Science, Minia University, El-Minia, Egypt) for using his digital Camera. I also thank Dr. Hossam EA (Zoology Department, Faculty of Science, Minia University, El-Minia, Egypt) for giving the whey protein.

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Authors and Affiliations

  1. Zoology Department, Faculty of Science, Minia University, 61519, El-Minia, Egypt

    Bahaa Kenawy Abuel-Hussien Abdel-Salam

  2. Biology Department, Deanship of Preparatory Year, Shaqra University, Shaqra, Kingdom of Saudi Arabia

    Bahaa Kenawy Abuel-Hussien Abdel-Salam

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Correspondence to Bahaa Kenawy Abuel-Hussien Abdel-Salam.

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Abdel-Salam, B.K.AH. Modulatory Effect of Whey Proteins in Some Cytokines Involved in Wound Healing in Male Diabetic Albino Rats. Inflammation 37, 1616–1622 (2014). https://doi.org/10.1007/s10753-014-9888-z

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  • DOI: https://doi.org/10.1007/s10753-014-9888-z

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