Skip to main content
SpringerLink
Log in

Advanced glycation end products promote differentiation of CD4+ T helper cells toward pro-inflammatory response

  • Published:
Journal of Huazhong University of Science and Technology [Medical Sciences] Aims and scope Submit manuscript

Summary

This study investigated the effect of advanced glycation end products (AGEs) on differentiation of naïve CD4+ T cells and the role of the receptor of AGEs (RAGE) and peroxisome proliferator-activated receptors (PPARs) activity in the process in order to gain insight into the mechanism of immunological disorders in diabetes. AGEs were prepared by the reaction of bovine serum albumin (BSA) with glucose. Human naïve CD4+ T cells, enriched from blood of healthy adult volunteers with negative selection assay, were cultured in vitro and treated with various agents including AGEs, BSA, high glucose, PGJ2 and PD68235 for indicated time. In short hairpin (sh) RNA knock-down experiment, naïve CD4+ T cells were transduced with media containing shRNA-lentivirus generated from lentiviral packaging cell line, Lent-XTM 293 T cells. Surface and intracellular cytokine stainings were used for examination of CD4+ T cell phenotypes, and real-time PCR and Western blotting for detection of transcription factor mRNA and protein expression, respectively. The suppressive function of regulatory T (Treg) cells was determined by a [3H]-thymidine incorporation assay. The results showed that AGEs induced higher pro-inflammatory Th1/Th17 cells differentiated from naïve CD4+ T cells than the controls, whereas did not affect anti-inflammatory Treg cells. However, AGEs eliminated suppressive function of Treg cells. In addition, AGEs increased RAGE mRNA expression in naïve CD4+ T cells, and RAGE knock-down by shRNA eliminated the effect of AGEs on the differentiation of CD4+ T cells and the reduction of suppressive function of Treg cells. Furthermore, AGEs inhibited the mRNA expression of PPARγ, not PPARα PPARγ agonist, PGJ2, inhibited the effect of AGEs on naïve CD4+ T cell differentiation and reversed the AGE-reduced suppressive function of Treg cells; on the other hand, PPARγ antagonist, PD68235, attenuated the blocking effect of RAGE shRNA on the role of AGEs. It was concluded that AGEs may promote CD4+ T cells development toward pro-inflammatory state, which is associated with increased RAGE mRNA expression and reduced PPARγ activity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. van Belle TL, Coppieters KT, von Herrath MG. Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiol Rev, 2011,91(1):79–118

    Article  Google Scholar 

  2. Ginter E, Simko V. Type 2 diabetes mellitus, pandemic in 21st century. Adv Exp Med Biol, 2012,771:42–50

    Google Scholar 

  3. Nikolajczyk BS, Jagannathan-Bogdan M, Shin H, et al. State of the union between metabolism and the immune system in type 2 diabetes. Genes Immun, 2011,12(4): 239–250

    Article  Google Scholar 

  4. Culina S, Brezar V, Mallone R. Insulin and type 1 diabetes: immune connections. Eur J Endocrinol, 2013,168(2): R19–R31

    Article  Google Scholar 

  5. Zhu J, Paul WE. Heterogeneity and plasticity of T helper cells. Cell Res, 2010,20(1):4–12

    Article  Google Scholar 

  6. Hirota K, Martin B, Veldhoen M. Development, regulation and functional capacities of Th17 cells. Semin Immunopathol, 2010,32(1):3–16

    Article  Google Scholar 

  7. Ohkura N, Kitagawa Y, Sakaguchi S. Development and maintenance of regulatory T cells. Immunity, 2013 38(3):414–423

    Article  Google Scholar 

  8. Zeng C, Shi X, Zhang B, et al. The imbalance of Th17/Th1/Treg in patients with type 2 diabetes: relationship with metabolic factors and complications. J Mol Med, 2012,2(90):175–186

    Google Scholar 

  9. Shao S, He F, Yang Y, et al. Th17 cells in type 1 diabetes. Cell Immun, 2012,1(280):16–21

    Google Scholar 

  10. Geerlings SE, Hoepelman AM. Immune dysfunction in patients with mellitus (DM). FEMS Immunol Med Microbiol, 1999,26(3–4):259–265

    Google Scholar 

  11. Thomas MC. Advanced glycation end products. Contrib Nephrol, 2011,170:66–74

    Article  Google Scholar 

  12. Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes, 2005,54(6):1615–1625

    Article  Google Scholar 

  13. Lin J, Tang Y, Kang Q, et al. Curcumin inhibits gene expression of receptor for advanced glycation end-products (RAGE) in hepatic stellate cells in vitro by elevating PPARγ activity and attenuating oxidative stress. Br J Pharmacol, 2012,166(8): 2212–2227

    Article  Google Scholar 

  14. Miele C, Riboulet A, Maitan MA, et al. Human glycated albumin affects glucose metabolism in L6 skeletal muscle cells by impairing insulin-induced insulin receptor substrate (IRS) signaling through protein kinase C alpha-mediated mechanism. J Biol Chem, 2003,278(48): 47 376–47 287

    Article  Google Scholar 

  15. Fraley S, Feng Y, Krishnamurthy R, et al. A distinctive role for focal adhesion proteins in three-dimensional cell motility. Nat Cell Biol, 2010,12(6):598–604

    Article  Google Scholar 

  16. Franke S, Rüster C, Pester J, et al. Advanced glycation end products affect growth and function of osteoblasts. Clin Exp Rheumatol, 2011,29(4):650–660

    Google Scholar 

  17. Sato T, Wu X, Shimogaito N, et al. Effects of high-AGE beverage on RAGE and VEGF expressions in the liver and kidneys. Eur J Nutr, 2009,48(1):6–11

    Article  Google Scholar 

  18. Poulsen L, Siersbaek M, Mandrup S. PPARs: fatty acid sensors controlling metabolism. Semin Cell Dev Biol, 2012,23(6):631–639

    Article  Google Scholar 

  19. Ahmadian M, Suh JM, Hah N, et al. PPARγ signaling and metabolism: the good, the bad and the future. Nat Med, 2013,19(5):557–566

    Google Scholar 

  20. Mahali SK, Manna SK. Beta-D-glucoside protects against advanced glycation end products (AGEs)-mediated diabetic responses by suppressing ERK and inducing PPAR gamma DNA binding. Biochem Pharmacol, 2012,84(12): 1681–1690

    Article  Google Scholar 

  21. Wang SH, Guo YJ, Yuan Y, et al. PPARγ-mediated advanced glycation end products regulate neural stem cell proliferation but not neural differentiation through the BDNF-CREB pathway. Toxicol Lett, 2011,206(3): 339–346

    Article  Google Scholar 

  22. Matsui T, Yamagishi S, Takeuchi M, et al. Nifedipine inhibits advanced glycation end products (AGEs) and their receptor (RAGE) interaction-mediated proximal tubular cell injury via peroxisome proliferator-activated receptor-gamma activation. Biochem Biophys Res Commun, 2010,398(2):326–330

    Article  Google Scholar 

  23. Wållberg M, Cooke A. Immune mechanisms in type 1 diabetes. Trends Immunol, 2013,12(34):583–591

    Google Scholar 

  24. Yamane H, Paul WE. Early signaling events that underlie fate decisions of naive CD4(+) T cells toward distinct T-helper cell subsets. Immunol Rev, 2013,252(1):12–23

    Article  Google Scholar 

  25. Kitagishi Y, Kobayashi M, Yamashina Y, et al. Elucidating the regulation of T cell subsets (review). Int J Mol Med, 2012,30(6):1255–1260

    Google Scholar 

  26. Wambre E, James EA, Kwok WW. Characterization of CD4+ T cell subsets in allergy. Curr Opin Immunol, 2012,24(6):700–706

    Article  Google Scholar 

  27. Serr I, Weigmann B, Franke RK, et al. Treg vaccination in autoimmune type 1 diabetes. BioDrugs, 2013 [Epub ahead of print]

    Google Scholar 

  28. Zong H, Ward M, Stitt AW. AGEs, RAGE, and diabetic retinopathy. Curr Diab Rep, 2011,11(4):244–252

    Article  Google Scholar 

  29. Cipolletta D, Feuerer M, Li A, et al. PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature, 2012,486(7404):549–553

    Google Scholar 

  30. Berger H, Végran F, Chikh M, et al. SOCS3 transactivation by PPARγ prevents IL-17-driven cancer growth. Cancer Res, 2013,73(12):3578–3590

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Xiao-qun Han  (韩晓群), Zuo-jiong Gong  (龚作炯), Xun Li  (李 汛) & Li-kun Wang  (王立坤)

  2. Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    San-qing Xu  (徐三清)

  3. Department of Infectious Diseases, Wuhan Medical Treatment Center, Wuhan, 430023, China

    Shi-min Wu  (伍仕敏), Jian-hong Wu  (吴建红) & Hua-fen Yang  (杨华芬)

Authors
  1. Xiao-qun Han  (韩晓群)
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zuo-jiong Gong  (龚作炯)
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. San-qing Xu  (徐三清)
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xun Li  (李 汛)
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Li-kun Wang  (王立坤)
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shi-min Wu  (伍仕敏)
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jian-hong Wu  (吴建红)
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hua-fen Yang  (杨华芬)
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zuo-jiong Gong  (龚作炯).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Han, Xq., Gong, Zj., Xu, Sq. et al. Advanced glycation end products promote differentiation of CD4+ T helper cells toward pro-inflammatory response. J. Huazhong Univ. Sci. Technol. [Med. Sci.] 34, 10–17 (2014). https://doi.org/10.1007/s11596-014-1224-1

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11596-014-1224-1

Key words

Search

Navigation