Cinnamon and Immune Actions: Potential Role in Tristetraprolin-Mediated Inflammatory Diseases

  • Heping CaoEmail author
Part of the Nutrition and Health book series (NH)

Key Points

Inflammatory diseases place a heavy burden on the American health care system. Tristetraprolin, a zinc-dependent mRNA binding protein decreases the stability of mRNAS coding for some proinflammatory cytokines. Tristetraprolin-deficient mice develop a profound inflammatory syndrome. Tristetraprolin is a potential cancer therapy due to its control of vascular endothelial growth factor mRNA stability. Cinnamon extract stimulates the expression of antiinflammatory tristetraprolin. Bioactive compound(s) in cinnamon extract define its molecular mechanisms. Cinnamon is potentially important in tristetraprolin-mediated inflammatory diseases.

Key Words

Cancer cinnamon immunity inflammation insulin macrophage obesity tristetraprolin 


  1. 1.
    Phillips K, Kedersha N, Shen L, Blackshear PJ, Anderson P (2004) Arthritis suppressor genes TIA-1 and TTP dampen the expression of tumor necrosis factor alpha, cyclooxygenase 2, and inflammatory arthritis. Proc Natl Acad Sci USA 101:2011–2016PubMedCrossRefGoogle Scholar
  2. 2.
    Taylor GA, Carballo E, Lee DM et al (1996) A pathogenetic role for TNF alpha in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency. Immunity 4:445–454PubMedCrossRefGoogle Scholar
  3. 3.
    Carballo E, Lai WS, Blackshear PJ (1998) Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin. Science 281:1001–1005PubMedCrossRefGoogle Scholar
  4. 4.
    Carballo E, Lai WS, Blackshear PJ (2000) Evidence that tristetraprolin is a physiological regulator of granulocyte-macrophage colony-stimulating factor messenger RNA deadenylation and stability. Blood 95:1891–1899PubMedGoogle Scholar
  5. 5.
    Ogawa K, Chen F, Kim YJ, Chen Y (2003) Transcriptional regulation of tristetraprolin by transforming growth factor-beta in human T cells. J Biol Chem 278:30373–30381PubMedCrossRefGoogle Scholar
  6. 6.
    Blackshear PJ (2002) Tristetraprolin and other CCCH tandem zinc-finger proteins in the regulation of mRNA turnover. Biochem Soc Trans 30:945–952PubMedCrossRefGoogle Scholar
  7. 7.
    Cao H, Deterding LJ, Blackshear PJ (2007) Phosphorylation site analysis of the anti-inflammatory and mRNA-destabilizing protein tristetraprolin. Expert Rev Proteomics 4:711–726PubMedCrossRefGoogle Scholar
  8. 8.
    Bakheet T, Frevel M, Williams BR, Greer W, Khabar KS (2001) ARED: human AU-rich element-containing mRNA database reveals an unexpectedly diverse functional repertoire of encoded proteins. Nucleic Acids Res 29:246–254PubMedCrossRefGoogle Scholar
  9. 9.
    Blackshear PJ, Lai WS, Kennington EA et al (2003) Characteristics of the interaction of a synthetic human tristetraprolin tandem zinc finger peptide with AU-rich element-containing RNA substrates. J Biol Chem 278:19947–19955PubMedCrossRefGoogle Scholar
  10. 10.
    Cao H, Dzineku F, Blackshear PJ (2003) Expression and purification of recombinant tristetraprolin that can bind to tumor necrosis factor-alpha mRNA and serve as a substrate for mitogen-activated protein kinases. Arch Biochem Biophys 412:106–120PubMedCrossRefGoogle Scholar
  11. 11.
    Cao H (2004) Expression, purification, and biochemical characterization of the antiinflammatory tristetraprolin: a zinc-dependent mRNA binding protein affected by posttranslational modifications. Biochemistry 43:13724–13738PubMedCrossRefGoogle Scholar
  12. 12.
    Carballo E, Cao H, Lai WS, Kennington EA, Campbell D, Blackshear PJ (2001) Decreased sensitivity of tristetraprolin-deficient cells to p38 inhibitors suggests the involvement of tristetraprolin in the p38 signaling pathway. J Biol Chem 276:42580–42587PubMedCrossRefGoogle Scholar
  13. 13.
    Lai WS, Carballo E, Strum JR, Kennington EA, Phillips RS, Blackshear PJ (1999) Evidence that tristetraprolin binds to AU-rich elements and promotes the deadenylation and destabilization of tumor necrosis factor alpha mRNA. Mol Cell Biol 19:4311–4323PubMedGoogle Scholar
  14. 14.
    Lai WS, Blackshear PJ (2001) Interactions of CCCH zinc finger proteins with mRNA: tristetraprolin- mediated AU-rich element-dependent mRNA degradation can occur in the absence of a poly(A) tail. J Biol Chem 276:23144–23154PubMedCrossRefGoogle Scholar
  15. 15.
    Worthington MT, Pelo JW, Sachedina MA, Applegate JL, Arseneau KO, Pizarro TT (2002) RNA binding properties of the AU-rich element-binding recombinant Nup475/TIS11/tristetraprolin protein. J Biol Chem 277:48558–48564PubMedCrossRefGoogle Scholar
  16. 16.
    Sawaoka H, Dixon DA, Oates JA, Boutaud O (2003) Tristetraprolin binds to the 3′-untranslated region of cyclooxygenase-2 mRNA. A polyadenylation variant in a cancer cell line lacks the binding site. J Biol Chem 278:13928–13935PubMedCrossRefGoogle Scholar
  17. 17.
    Sully G, Dean JL, Wait R et al (2004) Structural and functional dissection of a conserved destabilizing element of cyclo-oxygenase-2 mRNA: evidence against the involvement of AUF-1 [AU-rich element/poly(U)-binding/degradation factor-1], AUF-2, tristetraprolin, HuR (Hu antigen R) or FBP1 (far-upstream-sequence-element-binding protein 1). Biochem J 377:629–639PubMedCrossRefGoogle Scholar
  18. 18.
    Ogilvie RL, Abelson M, Hau HH, Vlasova I, Blackshear PJ, Bohjanen PR (2005) Tristetraprolin down-regulates IL-2 gene expression through AU-rich element-mediated mRNA decay. J Immunol 174:953–961PubMedGoogle Scholar
  19. 19.
    Suswam E, Li Y, Zhang X et al (2008) Tristetraprolin down-regulates interleukin-8 and vascular endothelial growth factor in malignant glioma cells. Cancer Res 68:674–682PubMedCrossRefGoogle Scholar
  20. 20.
    Stoecklin G, Tenenbaum SA, Mayo T et al (2008) Genome-wide analysis identifies interleukin-10 mRNA as target of tristetraprolin. J Biol Chem 283:11689–11699PubMedCrossRefGoogle Scholar
  21. 21.
    Ehlting C, Lai WS, Schaper F et al (2007) Regulation of suppressor of cytokine signaling 3 (SOCS3) mRNA stability by TNF-{alpha} involves activation of the MKK6/p38MAPK/MK2 cascade. J Immunol 178:2813–2826PubMedGoogle Scholar
  22. 22.
    Frasca D, Landin AM, Alvarez JP, Blackshear PJ, Riley RL, Blomberg BB (2007) Tristetraprolin, a negative regulator of mRNA stability, is increased in old B cells and is involved in the degradation of e47 mRNA. J Immunol 179:918–927PubMedGoogle Scholar
  23. 23.
    Yu H, Stasinopoulos S, Leedman P, Medcalf RL (2003) Inherent instability of plasminogen activator inhibitor type 2 mRNA is regulated by tristetraprolin. J Biol Chem 278:13912–13918PubMedCrossRefGoogle Scholar
  24. 24.
    Cao H, Tuttle JS, Blackshear PJ (2004) Immunological characterization of tristetraprolin as a low abundance, inducible, stable cytosolic protein. J Biol Chem 279:21489–21499PubMedCrossRefGoogle Scholar
  25. 25.
    Lai WS, Stumpo DJ, Blackshear PJ (1990) Rapid insulin-stimulated accumulation of an mRNA encoding a proline-rich protein. J Biol Chem 265:16556–16563PubMedGoogle Scholar
  26. 26.
    Cao H, Deterding LJ, Venable JD et al (2006) Identification of the anti-inflammatory protein tristetraprolin as a hyperphosphorylated protein by mass spectrometry and site-directed mutagenesis. Biochem J 394:285–297PubMedCrossRefGoogle Scholar
  27. 27.
    Cao H, Lin R (2008) Phosphorylation of recombinant tristetraprolin in vitro. Protein J 27:163–169PubMedCrossRefGoogle Scholar
  28. 28.
    Chrestensen CA, Schroeder MJ, Shabanowitz J et al (2004) MAPKAP kinase 2 phosphorylates tristetraprolin on in vivo sites including Ser178, a site required for 14-3-3 binding. J Biol Chem 279:10176–10184PubMedCrossRefGoogle Scholar
  29. 29.
    Carrick DM, Blackshear PJ (2007) Comparative expression of tristetraprolin (TTP) family member transcripts in normal human tissues and cancer cell lines. Arch Biochem Biophys 462:278–285PubMedCrossRefGoogle Scholar
  30. 30.
    Essafi-Benkhadir K, Onesto C, Stebe E, Moroni C, Pages G (2007) Tristetraprolin inhibits Ras-dependent tumor vascularization by inducing VEGF mRNA degradation. Mol Biol Cell 18:4648–4658PubMedCrossRefGoogle Scholar
  31. 31.
    Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676PubMedCrossRefGoogle Scholar
  32. 32.
    Goldberg-Cohen I, Furneauxb H, Levy AP (2002) A 40-bp RNA element that mediates stabilization of vascular endothelial growth factor mRNA by HuR. J Biol Chem 277:13635–13640PubMedCrossRefGoogle Scholar
  33. 33.
    Shih SC, Claffey KP (1999) Regulation of human vascular endothelial growth factor mRNA stability in hypoxia by heterogeneous nuclear ribonucleoprotein L. J Biol Chem 274:1359–1365PubMedCrossRefGoogle Scholar
  34. 34.
    Ciais D, Cherradi N, Bailly S et al (2004) Destabilization of vascular endothelial growth factor mRNA by the zinc-finger protein TIS11b. Oncogene 23:8673–8680PubMedCrossRefGoogle Scholar
  35. 35.
    Bouchard L, Tchernof A, Deshaies Y et al (2007) ZFP36: a promising candidate gene for obesity-related metabolic complications identified by converging genomics. Obes Surg 17:372–382PubMedCrossRefGoogle Scholar
  36. 36.
    Bouchard L, Vohl MC, Deshaies Y, Rheaume C, Daris M, Tchernof A (2007) Visceral adipose tissue zinc finger protein 36 mRNA levels are correlated with insulin, insulin resistance index, and adiponectinemia in women. Eur J Endocrinol 157:451–457PubMedCrossRefGoogle Scholar
  37. 37.
    Cao H, Polansky MM, Anderson RA (2007) Cinnamon extract and polyphenols affect the expression of tristetraprolin, insulin receptor, and glucose transporter 4 in mouse 3T3-L1 adipocytes. Arch Biochem Biophys 459:214–222PubMedCrossRefGoogle Scholar
  38. 38.
    Cao H, Urban JF Jr, Anderson RA (2008) Insulin increases tristetraprolin and decreases VEGF gene expression in mouse 3T3-L1 adipocytes. Obesity (Silver Spring) 16:1208–1218CrossRefGoogle Scholar
  39. 39.
    Lin NY, Lin CT, Chen YL, Chang CJ (2007) Regulation of tristetraprolin during differentiation of 3T3-L1 preadipocytes. FEBS J 274:867–878PubMedCrossRefGoogle Scholar
  40. 40.
    Thalmeier A, Dickmann M, Giegling I et al (2008) Gene expression profiling of post-mortem orbitofrontal cortex in violent suicide victims. Int J Neuropsychopharmacol 11:217–228PubMedCrossRefGoogle Scholar
  41. 41.
    Lai WS, Parker JS, Grissom SF, Stumpo DJ, Blackshear PJ (2006) Novel mRNA targets for tristetraprolin (TTP) identified by global analysis of stabilized transcripts in TTP-deficient fibroblasts. Mol Cell Biol 26:9196–9208PubMedCrossRefGoogle Scholar
  42. 42.
    Taylor GA, Blackshear PJ (1995) Zinc inhibits turnover of labile mRNAs in intact cells. J Cell Physiol 162:378–387PubMedCrossRefGoogle Scholar
  43. 43.
    Cousins RJ, Blanchard RK, Popp MP et al (2003) A global view of the selectivity of zinc deprivation and excess on genes expressed in human THP-1 mononuclear cells. Proc Natl Acad Sci USA 100:6952–6957PubMedCrossRefGoogle Scholar
  44. 44.
    Cao H, Lin R, Ghosh S, Anderson RA, Urban JF Jr (2008) Production and characterization of ZFP36L1 antiserum against recombinant protein from Escherichia coli. Biotechnol Prog 24:326–333PubMedCrossRefGoogle Scholar
  45. 45.
    Nishimura S, Manabe I, Nagasaki M et al (2007) Adipogenesis in obesity requires close interplay between differentiating adipocytes, stromal cells and blood vessels. Diabetes 56:1517–1526PubMedCrossRefGoogle Scholar
  46. 46.
    Tilg H, Moschen AR (2006) Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 6:772–783PubMedCrossRefGoogle Scholar
  47. 47.
    Ferrara N, Kerbel RS (2005) Angiogenesis as a therapeutic target. Nature 438:967–974PubMedCrossRefGoogle Scholar
  48. 48.
    Broadhurst CL, Polansky MM, Anderson RA (2000) Insulin-like biological activity of culinary and medicinal plant aqueous extracts in vitro. J Agric Food Chem 48:849–852PubMedCrossRefGoogle Scholar
  49. 49.
    Khan A, Safdar M, Ali Khan MM, Khattak KN, Anderson RA (2003) Cinnamon improves glucose and lipids of people with type 2 diabetes. Diab Care 26:3215–3218CrossRefGoogle Scholar
  50. 50.
    Vanschoonbeek K, Thomassen BJ, Senden JM, Wodzig WK, van Loon LJ (2006) Cinnamon supplementation does not improve glycemic control in postmenopausal type 2 diabetes patients. J Nutr 136:977–980PubMedGoogle Scholar
  51. 51.
    Baker WL, Gutierrez-Williams G, White CM, Kluger J, Coleman CI (2008) Effect of cinnamon on glucose control and lipid parameters. Diab Care 31:41–43CrossRefGoogle Scholar
  52. 52.
    Anderson RA, Broadhurst CL, Polansky MM et al (2004) Isolation and characterization of polyphenol type-A polymers from cinnamon with insulin-like biological activity. J Agric Food Chem 52:65–70PubMedCrossRefGoogle Scholar
  53. 53.
    Shoji T, Masumoto S, Moriichi N et al (2006) Apple procyanidin oligomers absorption in rats after oral administration: analysis of procyanidins in plasma using the porter method and high-performance liquid chromatography/tandem mass spectrometry. J Agric Food Chem 54:884–892PubMedCrossRefGoogle Scholar
  54. 54.
    Imparl-Radosevich J, Deas S, Polansky MM et al (1998) Regulation of PTP-1 and insulin receptor kinase by fractions from cinnamon: implications for cinnamon regulation of insulin signalling. Horm Res 50:177–182PubMedCrossRefGoogle Scholar
  55. 55.
    Jarvill-Taylor KJ, Anderson RA, Graves DJ (2001) A hydroxychalcone derived from cinnamon functions as a mimetic for insulin in 3T3-L1 adipocytes. J Am Coll Nutr 20:327–336PubMedGoogle Scholar
  56. 56.
    Zhu W, Brauchle MA, Di Padova F et al (2001) Gene suppression by tristetraprolin and release by the p38 pathway. Am J Physiol Lung Cell Mol Physiol 281:499–508Google Scholar
  57. 57.
    Deleault KM, Skinner SJ, Brooks SA (2007) Tristetraprolin regulates TNF TNF-alpha mRNA stability via a proteasome dependent mechanism involving the combined action of the ERK and p38 pathways. Mol Immunol 56:2160–2169Google Scholar
  58. 58.
    Cao H, Urban JF Jr, Anderson RA (2008) Cinnamon polyphenol extract affects immune responses by regulating anti- and proinflammatory and glucose transporter gene expression in mouse macrophages. J Nutr 138:833–840PubMedGoogle Scholar
  59. 59.
    Preuss HG, Echard B, Polansky MM, Anderson R (2006) Whole cinnamon and aqueous extracts ameliorate sucrose-induced blood pressure elevations in spontaneously hypertensive rats. J Am Coll Nutr 25:144–150PubMedGoogle Scholar
  60. 60.
    Qin B, Nagasaki M, Ren M, Bajotto G, Oshida Y, Sato Y (2003) Cinnamon extract (traditional herb) potentiates in vivo insulin-regulated glucose utilization via enhancing insulin signaling in rats. Diabetes Res Clin Pract 62:139–148PubMedCrossRefGoogle Scholar
  61. 61.
    Qin B, Nagasaki M, Ren M, Bajotto G, Oshida Y, Sato Y (2004) Cinnamon extract prevents the insulin resistance induced by a high-fructose diet. Horm Metab Res 36:119–125PubMedCrossRefGoogle Scholar
  62. 62.
    Verspohl EJ, Bauer K, Neddermann E (2005) Antidiabetic effect of Cinnamomum cassia and Cinnamomum zeylanicum in vivo and in vitro. Phytother Res 19:203–206PubMedCrossRefGoogle Scholar
  63. 63.
    Hlebowicz J, Darwiche G, Bjorgell O, Almer LO (2007) Effect of cinnamon on postprandial blood glucose, gastric emptying, and satiety in healthy subjects. Am J Clin Nutr 85:1552–1556PubMedGoogle Scholar
  64. 64.
    Cao H, Urban JF Jr, Anderson RA (2007) Prevention of obesity by plant polyphenols via tristetraprolin-mediated cytokine mRNA instability. Obesity 15[9], A90Google Scholar
  65. 65.
    Cao H, Hininger-Favier I, Kelly MA et al (2007) Green tea polyphenol extract regulates the expression of genes involved in glucose uptake and insulin signaling in rats fed a high fructose diet. J Agric Food Chem 55:6372–6378PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.US Department of Agriculture, Commodity Utilization Research Unit, Southern Regional Research CenterAgricultural Research ServiceNew OrleansUSA

Personalised recommendations