Peroxisome proliferator-activated receptor-γ and thymic stromal lymphopoietin are involved in the pathophysiology of childhood coeliac disease
- 432 Downloads
Celiac disease (CD) is a chronic autoimmune enteropathy caused by exposure to dietary gluten in genetically predisposed individuals. The transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) was shown to exert protective effects in several immune-mediated disorders. Activation of PPARγ suppressed the expression of thymic stromal lymphopoietin (TSLP), an inducer of proinflammatory cytokines. Since the role of TSLP in gluten-sensitive enteropathy is completely unknown, we investigated the involvement of TSLP and its regulator PPARγ in childhood CD. We collected duodenal biopsy specimens from 19 children with newly diagnosed CD, 6 children with treated CD (gluten-free diet, GFD), and 10 controls. Expression of mRNA and protein levels of PPARγ, TSLP, and TSLP receptor were determined by real-time RT-PCR and Western blot, respectively. Duodenal localization of PPARγ and TSLP was studied by immunohistochemistry. In duodenal mucosa of children with CD, the amount of PPARγ was significantly lower and simultaneously that of TSLP significantly higher compared to controls (p < 0.05). In GFD-treated patients, the levels of PPARγ mRNA and protein were significantly higher while that of TSLP markedly lower compared to newly diagnosed CD (p < 0.05). Immunohistochemistry revealed PPARγ and TSLP expression in lamina propria immune cells and in enterocytes. Low expression of PPARγ and high expression of TSLP in the duodenal mucosa of children with newly diagnosed CD suggest that they are involved in the pathophysiology of CD. We hypothesize that PPARγ may be an inhibitory regulator of TSLP-stimulated inflammatory processes in CD.
KeywordsTSLP PPARγ Coeliac disease Children Duodenal biopsies
We are grateful to Mária Bernáth and Erika Sklánitz Samodai for their excellent technical assistance. This work was supported by Hungarian National Scientific Research Foundation Grant-OTKA-K81117, -84087/2010, -K105530, -PD83431, -PD105361; Lendulet Research Grant-LP2011-008, 2011; TÁMOP 4.2.2. B-10/1-2010-2013. Ádám Vannay and Gábor Veres are holders of the János Bolyai Research grant; this work was supported by the János Bolyai Research Scholarschip of the Hungarian Academy of Sciences.
Conflict of interest
The authors declare that they have no conflict of interest.
- 1.Barroso E, Eyre E, Palomer X, Vazquez-Carrera M (2011) The peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) agonist GW501516 prevents TNF-alpha-induced NF-kappaB activation in human HaCaT cells by reducing p65 acetylation through AMPK and SIRT1. Biochem Pharmacol 81:534–543. doi: 10.1016/j.bcp.2010.12.004 PubMedCrossRefGoogle Scholar
- 3.Christmann RB, Mathes A, Affandi AJ, Padilla C, Nazari B, Bujor AM, Stifano G, Lafyatis R (2013) Thymic stromal lymphopoietin is up-regulated in the skin of patients with systemic sclerosis and induces profibrotic genes and intracellular signaling that overlap with those induced by interleukin-13 and transforming growth factor beta. Arthritis Rheum 65:1335–1346. doi: 10.1002/art.37859 PubMedCrossRefGoogle Scholar
- 5.Cuzzocrea S, Pisano B, Dugo L, Ianaro A, Maffia P, Patel NS, Di Paola R, Ialenti A, Genovese T, Chatterjee PK, Di Rosa M, Caputi AP, Thiemermann C (2004) Rosiglitazone, a ligand of the peroxisome proliferator-activated receptor-gamma, reduces acute inflammation. Eur J Pharmacol 483:79–93PubMedCrossRefGoogle Scholar
- 10.Husby S, Koletzko S, Korponay-Szabo IR, Mearin ML, Phillips A, Shamir R, Troncone R, Giersiepen K, Branski D, Catassi C, Lelgeman M, Maki M, Ribes-Koninckx C, Ventura A, Zimmer KP, Diagnosis EWGoCD, Committee EG, European Society for Pediatric Gastroenterology H, Nutrition (2012) European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr 54:136–160. doi: 10.1097/MPG.0b013e31821a23d0 PubMedCrossRefGoogle Scholar
- 11.Jung K, Tanaka A, Fujita H, Matsuda A, Oida K, Karasawa K, Okamoto N, Ohmori K, Jee Y, Shin T, Matsuda H (2011) Peroxisome proliferator-activated receptor gamma-mediated suppression of dendritic cell function prevents the onset of atopic dermatitis in NC/Tnd mice. J Allergy Clin Immunol 127(420–429):e421–e426. doi: 10.1016/j.jaci.2010.10.043 Google Scholar
- 15.Luciani A, Villella VR, Vasaturo A, Giardino I, Pettoello-Mantovani M, Guido S, Cexus ON, Peake N, Londei M, Quaratino S, Maiuri L (2010) Lysosomal accumulation of gliadin p31-43 peptide induces oxidative stress and tissue transglutaminase-mediated PPARgamma downregulation in intestinal epithelial cells and coeliac mucosa. Gut 59:311–319. doi: 10.1136/gut.2009.183608 PubMedCrossRefGoogle Scholar
- 17.Sharabi Y, Oron-Herman M, Kamari Y, Avni I, Peleg E, Shabtay Z, Grossman E, Shamiss A (2007) Effect of PPAR-gamma agonist on adiponectin levels in the metabolic syndrome: lessons from the high fructose fed rat model. Am J Hypertens 20:206–210. doi: 10.1016/j.amjhyper.2006.08.002 PubMedCrossRefGoogle Scholar
- 19.Soares FL, de Oliveira MR, Teixeira LG, Menezes Z, Pereira SS, Alves AC, Batista NV, de Faria AM, Cara DC, Ferreira AV, Alvarez-Leite JI (2013) Gluten-free diet reduces adiposity, inflammation and insulin resistance associated with the induction of PPAR-alpha and PPAR-gamma expression. J Nutr Biochem 24:1105–1111. doi: 10.1016/j.jnutbio.2012.08.009 PubMedCrossRefGoogle Scholar
- 20.Sziksz E, Vörös P, Veres G, Fekete A, Vannay Á (2013) Coeliac disease: from triggering factors to treatment. Int J Celiac Dis 1:9–13Google Scholar
- 23.Vannay A, Sziksz E, Prokai A, Veres G, Molnar K, Szakal DN, Onody A, Korponay-Szabo IR, Szabo A, Tulassay T, Arato A, Szebeni B (2010) Increased expression of hypoxia-inducible factor 1alpha in coeliac disease. Pediatr Res 68:118–122. doi: 10.1203/00006450-201011001-0022710.1203/PDR.0b013e3181e5bc96 PubMedCrossRefGoogle Scholar