Thymic stromal lymphopoetin (TSLP), the long and short of it

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220px-pistacia_lentiscusDr Carrie Decker ND, explores the relationship between a molecular communication chemical and human health, its remediation and the role of natural agents in the facilitation of this, with a particular emphasis on the emerging potential of Mastic (Greek: Μαστίχα) a resin obtained from the mastic tree (Pistacia lentiscus).

Thymic stromal lymphopoetin (TSLP) is cytokine of importance in the realm of inflammation and immunoregulation, yet is less often discussed than the more well-known interleukins, interferons, and tumor necrosis factors. TSLP was first discovered in 1994 as a protein secreted from thymic stromal cell lines, and found to support B-cell differentiation and growth.[1] Only very recently in 2015 was there found to be a short form (sfTSLP) and a long form (lfTSLP), which have very opposite effects.[2],[3] The lfTSLP is proinflammatory, activates mast cells, DCs, and T cells, and is only expressed during inflammation.[4] The sfTSLP is expressed during steady-state conditions, downregulated with inflammation, and inhibits cytokine secretion of DCs.  Both forms can be produced by epithelial and dendritic cells (DCs), and are expressed by the tissues of the skin, oral mucosa, salivary glands, and intestine. They also both have antimicrobial activity, with sfTSLP having a stronger effect.[5] Research up until the discovery of the different short and long forms in 2015 has focused on the long form, which herein will simply be referred to as TSLP to be in agreement with published research unless the short form or long form is specified.

In vivo, lfTSLP is upregulated in conditions such as atopic dermatitis, asthma, ulcerative colitis, while it is absent in healthy tissues. These inflammatory conditions appear to have the opposite effect on sfTSLP, which has been shown to be downregulated locally as observed in biopsies of tissue from individuals with atopic dermatitis and Crohn’s disease.[6] Low levels of both TSLP isoforms have also been observed in individuals with untreated or refractory coeliac disease in comparison to treated coeliac disease and controls, which may be a consequence of enterocyte loss, or increased production of a protein which degrades TSLP.[7] Environmental factors such as viruses, microbes, helminths, allergen sources, diesel exhaust, cigarette smoke, and chemicals trigger lfTSLP production.[8] lfTSLP has been shown experimentally to be induced by inflammatory Th2 cytokines such as IL-13 and IL-4 in bronchial epithelial cells and nasal mucosa, and also induced by rhinovirus infection.[9],[10] lfTSLP is upregulated in the intestinal epithelial cell line Caco-2 by challenge with Salmonella typhimurium, while vitamin D3 activates promotor regions and induces sfTSLP transcription. TSLP is overexpressed in esophageal biopsies from individuals with eosinophilic esophagitis, and chicken egg ovalbumin has been observed to induce TSLP secretion.[11]

The induction of lfTSLP with infection and antigen exposure further sheds light on how these mediators can worsen symptoms associated with a chronic inflammatory state such as asthma, allergies, or inflammatory bowel disease. Because lfTSLP further activates mast cells, DCs, and T cells, and is further increased by some of the cytokines they secrete, one can understand how this would worsen an already inflammatory state. Strategies of reducing lfTSLP or blocking its receptor have been investigated as a means for reducing an allergic or asthmatic state.[12],[13] Additionally, as sfTSLP has been shown to be low in disease states, and treatment with sfTSLP has been shown to have a protective effect in animal models,[14] this also may be utilised to mediate inflammatory conditions.

TSLP in breast milk and relationship with allergies

TSLP is present in breast milk, and has been shown to be much higher in the initial days after birth than at 11 – 26 days postpartum.[15]  Studies have investigated its impact on conditions such as allergies and asthma in paediatrics. A population study investigating relationships between residential areas, diet, and amount of TSLP in colostrum showed that TSLP levels were significantly higher (levels of magnitude) in women from Japan than Nepal, and that higher levels were associated with milk consumption during pregnancy, and lower levels were associated with yogurt consumption.[16] TSLP induces a Th2 response, and also is increased by Th2 related cytokines. The Nepalese have a very low incidence of allergies compared to individuals in Japan. These findings support the “hygiene hypothesis” of allergy, as high levels of sanitation such as in Japan are associated with lower exposure to infectious pathogens, and therefore a lower Th1 relative to Th2 response.

Impact of natural agents on TSLP

Glucocorticoids reduce the proinflammatory TSLP expression, much as they would be expected to. Other things which have been shown to inhibit TSLP include selenium,[17] berberine,[18] grapefruit juice,[19] and green tea extract.[20] Some agents which suppress the Th2 response or overall inflammation also act to reduce TSLP.  This includes the probiotic Lactobacillus rhamnosus and curcumin.[21],[22] Low-dose light-emitting diode (LED) therapy applied via a water bath to the lesions of atopic dermatitis in mice has been shown improve lesions in conjunction with reducing the infiltration of inflammatory cells and levels of TSLP, total IgE, nitric oxide, and histamine.[23] As was mentioned, vitamin D3 has been shown to increase the anti-inflammatory sfTSLP expression in keratinocytes, which may be one mechanism by which vitamin D can improve symptoms of atopic dermatitis.

Mastic gum has a long history of use for its antioxidant, anti-inflammatory, and antimicrobial effects, including bactericidal action against Helicobacter pylori.[24],[25] Interestingly, mastic gum has been shown to have positive impact on Crohn’s disease, however the potential involvement of TSLP was not investigated in this study.[26] Mastic gum has also been shown to reduce eosinophilia, airway hyper-responsiveness, and production of proinflammatory cytokines in a mouse model of asthma.[27] The impact of mastic gum on the secretion of TSLP in the asthmatic airway has been recently investigated.[28] In normal human bronchial cells cultured with IL-4 and IL-13, the presence of mastic gum was found to reduce mRNA expression of TSLP when subject to viral stimulation of the innate inflammatory response. Mastic gum was also observed to reduce bronchial expression of TSLP and interleukin (IL)-8 (promotor of neutrophil recruitment and degranulation) when challenged with viral stimuli in the absence of the Th2 related cytokines IL-4 and IL-13. Thus, it may support the reduction of allergy or asthma symptoms which worsen with viral infection, as increased TSLP levels promote a Th2 response.

Other botanicals with common use in other cultures have also been shown to reduce cytokine mediators of allergy including TSLP. Schizandrin, the bioactive agent found in the Chinese five-flavor berry Schisandra chinensis, has been shown to inhibite the production and mRNA expression of TSLP in human mast cell lines.[29] Atractylone, the active moiety of a Korean herb Pyeongwee-San, has also been shown to reduce cytokine mediators of allergy and inflammation including TSLP.[30] Bamboo salt, another traditional Korean treatment for allergies, also has been shown to decrease levels of TSLP in activated mast cells, with hydrogen sulfide being the active compound.[31] Tryptanthrin, an anti-inflammatory alkaloid derived from the Japanese indigo plant (Polygonum tinctorium Lour.) and other natural sources has been shown to reduce production of TSLP as well as inflammation and proliferation of mast cells stimulated by TSLP. [32],[33] It also was shown to reduce levels of histidine decarboxylase, histamine, IL-4 and IL-1β while improving lesions of atopic dermatitis.[34]

References

[1] Friend SL, et al. A thymic stromal cell line supports in vitro development of surface IgM+ B cells and produces a novel growth factor affecting B and T lineage cells. Exp Hematol. 1994 Mar;22(3):321-8. View Abstract

[2] Bjerkan L, et al. The short form of TSLP is constitutively translated in human keratinocytes and has characteristics of an antimicrobial peptide. Mucosal Immunol. 2015 Jan;8(1):49-56. View Abstract

[3] Fornasa G, et al. Dichotomy of short and long thymic stromal lymphopoietin isoforms in inflammatory disorders of the bowel and skin. J Allergy Clin Immunol. 2015 Aug;136(2):413-22. View Full Paper

[4] Bjerkan L, et al. Multiple Functions of the New Cytokine-Based Antimicrobial Peptide Thymic Stromal Lymphopoietin (TSLP). Pharmaceuticals (Basel). 2016 Jul 5;9(3). View Full Paper

[5] Bjerkan L, et al. The short form of TSLP is constitutively translated in human keratinocytes and has characteristics of an antimicrobial peptide. Mucosal Immunol. 2015 Jan;8(1):49-56. View Abstract

[6] Fornasa G, et al. Dichotomy of short and long thymic stromal lymphopoietin isoforms in inflammatory disorders of the bowel and skin. J Allergy Clin Immunol. 2015 Aug;136(2):413-22. View Full Paper

[7] Biancheri P, et al. Abnormal thymic stromal lymphopoietin expression in the duodenal mucosa of patients with coeliac disease. Gut. 2016 Oct;65(10):1670-80. View Full Paper

[8] Takai T. TSLP expression: cellular sources, triggers, and regulatory mechanisms. Allergol Int. 2012 Mar;61(1):3-17. View Abstract

[9] Kato A, et al. TLR3- and Th2 cytokine-dependent production of thymic stromal lymphopoietin in human airway epithelial cells. J Immunol. 2007 Jul 15;179(2):1080-7. View Full Paper

[10] Melum GR, et al. A thymic stromal lymphopoietin-responsive dendritic cell subset mediates allergic responses in the upper airway mucosa. J Allergy Clin Immunol. 2014 Sep;134(3):613-621.e7. View Abstract

[11] Chandramouleeswaran PM, et al. Preferential Secretion of Thymic Stromal Lymphopoietin (TSLP) by Terminally Differentiated Esophageal Epithelial Cells: Relevance to Eosinophilic Esophagitis (EoE). PLoS One. 2016 Mar 18;11(3):e0150968. View Full Paper

[12] Wang WL, et al. Thymic stromal lymphopoietin: a promising therapeutic target for allergic diseases. Int Arch Allergy Immunol. 2013;160(1):18-26. View Abstract

[13] Cheng DT, et al. Thymic stromal lymphopoietin receptor blockade reduces allergic inflammation in a cynomolgus monkey model of asthma. J Allergy Clin Immunol. 2013 Aug;132(2):455-62. View Abstract

[14] Fornasa G, et al. Dichotomy of short and long thymic stromal lymphopoietin isoforms in inflammatory disorders of the bowel and skin. J Allergy Clin Immunol. 2015 Aug;136(2):413-22. View Full Paper

[15] Macfarlane TV, et al. Thymic stromal lymphopoietin is present in human breast milk. Pediatr Allergy Immunol. 2010 Mar;21(2 Pt 2):e454-6. View Abstract

[16] Aihara Y, et al. Residential area, birth order, and dietary habit may influence TSLP levels in colostrum: comparative study between Japan and Nepal. Allergol Int. 2014 Jun;63(2):283-5. View Full Paper

[17] Moon PD, Kim HM. The suppression of thymic stromal lymphopoietin expression by selenium. Amino Acids. 2011 Nov 16. View Abstract

[18] Moon PD, et al. Berberine inhibits the production of thymic stromal lymphopoietin by the blockade of caspase-1/NF-κB pathway in mast cells. Int Immunopharmacol. 2011 Nov;11(11):1954-9. Epub 2011 Aug 19. View Abstract

[19] Moon PD, et al. Naringenin suppresses the production of thymic stromal lymphopoietin through the blockade of RIP2 and caspase-1 signal cascade in mast cells. Eur J Pharmacol. 2011 Dec 5;671(1-3):128-32. Epub 2011 Sep 24. View Abstract

[20] Moon PD, Choi IH, Kim HM. Epigallocatechin-3-O-gallate inhibits the production of thymic stromal lymphopoietin by the blockade of caspase-1/NF-κB pathway in mast cells. Amino Acids. 2011 Aug 11. View Abstract

[21] Kim HJ, et al. Effects of Lactobacillus rhamnosus on allergic march model by suppressing Th2, Th17, and TSLP responses via CD4(+)CD25(+)Foxp3(+) Tregs. Clin Immunol. 2014 Jul;153(1):178-86. View Abstract

[22] Moon PD, et al. Down-regulation of thymic stromal lymphopoietin by curcumin. Pharmacol Rep. 2013;65(2):525-31. View Abstract

[23] Kim CH, et al. Effects of low-dose light-emitting-diode therapy in combination with water bath for atopic dermatitis in NC/Nga mice. Photodermatol Photoimmunol Photomed. 2016 Jan;32(1):34-43. View Abstract

[24] Paraschos S, et al. Chios gum mastic: A review of its biological activities. Curr Med Chem. 2012;19(14):2292-302. View Abstract

[25] Dabos KJ, et al. The effect of mastic gum on Helicobacter pylori: a randomized pilot study. Phytomedicine. 2010 Mar 31;17(3):2. View Abstract

[26] Kaliora AC, et al. Chios mastic treatment of patients with active Crohn’s disease. World J Gastroenterol. 2007 Feb 7;13(5):748-53. View Full Paper

[27] Qiao J, et al. Mastic alleviates allergic inflammation in asthmatic model mice by inhibiting recruitment of eosinophils. Am J Respir Cell Mol Biol. 2011 Jul;45(1):95-100. View Abstract

[28] Cui KH. Mastic gum suppresses secretion of thymic stromal lymphopoietin in the asthmatic airway via NF-κB signaling pathway. Int J Clin Exp Med. 2016;9(8):15900-6. View Full Paper

[29] Moon PD, et al. Effects of schizandrin on the expression of thymic stromal lymphopoietin in human mast cell line HMC-1. Life Sci. 2012 Oct 5;91(11-12):384-8. View Abstract

[30] Kim HY, et al. Atractylone, an active constituent of KMP6, attenuates allergic inflammation on allergic rhinitis in vitro and in vivo models. Mol Immunol. 2016 Sep 13;78:121-132. View Abstract

[31] Han NR, et al. Hydrogen sulfide diminishes the levels of thymic stromal lymphopoietin in activated mast cells. Arch Dermatol Res. 2016 Mar;308(2):103-13. View Abstract

[32] Jahng Y. Progress in the studies on tryptanthrin, an alkaloid of history. Arch Pharm Res. 2013 May;36(5):517-35. View Abstract.

[33] Han NR, et al. Tryptanthrin reduces mast cell proliferation promoted by TSLP through modulation of MDM2 and p53. Biomed Pharmacother. 2016 Apr;79:71-7. View Abstract

[34] Han NR, et al. Tryptanthrin ameliorates atopic dermatitis through down-regulation of TSLP. Arch Biochem Biophys. 2014 Jan 15;542:14-20. View Abstract

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