Children with autism spectrum disorders, who improved with a luteolin-containing dietary formulation, show reduced serum levels of TNF and IL-6

I Tsilioni; A Taliou; K Francis; T C Theoharides

doi:10.1038/tp.2015.142

journal article Open Access Sep 29, 2015

Children with autism spectrum disorders, who improved with a luteolin-containing dietary formulation, show reduced serum levels of TNF and IL-6

I Tsilioni A Taliou K Francis T C Theoharides

Translational Psychiatry Vol. 5 No. 9 pp. e647-e647 · Springer Science and Business Media LLC

View at Publisher Save 10.1038/tp.2015.142

Abstract

AbstractAutism spectrum disorders (ASDs) have been associated with brain inflammation as indicated by microglia activation, as well as brain expression and increased plasma levels of interleukin-6 (IL-6) and tumor necrosis factor (TNF). Here we report that serum levels of IL-6 and TNF were elevated (61.95±94.76 pg ml−1and 313.8±444.3 pg ml−1, respectively) in the same cohort of patients with elevated serum levels of corticotropin-releasing hormone (CRH) and neurotensin (NT), while IL-9, IL-31 and IL-33 were not different from controls. The elevated CRH and NT levels did not change after treatment with a luteolin-containing dietary formulation. However, the mean serum IL-6 and TNF levels decreased significantly (P=0.036 andP=0.015, respectively) at the end of the treatment period (26 weeks) as compared with levels at the beginning; these decreases were strongly associated with children whose behavior improved the most after luteolin formulation treatment. Our results indicate that there are distinct subgroups of children within the ASDs that may be identifiable through serum levels of IL-6 and TNF and that these cytokines may constitute distinct prognostic markers for at least the beneficial effect of luteolin formulation.

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References

86

[1]

Fombonne E . Epidemiology of pervasive developmental disorders. Pediatr Res 2009; 65: 591–598. 10.1203/pdr.0b013e31819e7203

[2]

Johnson CP, Myers SM . Identification and evaluation of children with autism spectrum disorders. Pediatrics 2007; 120: 1183–1215. 10.1542/peds.2007-2361

[3]

McPartland J, Volkmar FR . Autism and related disorders. Handb Clin Neurol 2012; 106: 407–418. 10.1016/b978-0-444-52002-9.00023-1

[4]

Abrahams BS, Geschwind DH . Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet 2008; 9: 341–355. 10.1038/nrg2346

[5]

Centers for Disease Control and Prevention. CDC estimates 1 in 68 children has been identified with autism spectrum disorder, 2014. http://www.cdcgov/media/releases/2014/p0327-autism-spectrum-disorderhtml.

[6]

Hornig M, Weissenbock H, Horscroft N, Lipkin WI . An infection-based model of neurodevelopmental damage. Proc Natl Acad Sci USA 1999; 96: 12102–12107. 10.1073/pnas.96.21.12102

[7]

Hsiao EY, McBride SW, Chow J, Mazmanian SK, Patterson PH . Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proc Natl Acad Sci USA 2012; 109: 12776–12781. 10.1073/pnas.1202556109

[8]

Blenner S, Reddy A, Augustyn M . Diagnosis and management of autism in childhood. BMJ 2011; 343: d6238. 10.1136/bmj.d6238

[9]

Deth R, Muratore C, Benzecry J, Power-Charnitsky VA, Waly M . How environmental and genetic factors combine to cause autism: a redox/methylation hypothesis. NeuroToxicol 2008; 29: 190–201. 10.1016/j.neuro.2007.09.010

[10]

Herbert MR . Contributions of the environment and environmentally vulnerable physiology to autism spectrum disorders. Curr Opin Neurol 2010; 23: 103–110. 10.1097/wco.0b013e328336a01f

[11]

Rossignol DA, Genuis SJ, Frye RE . Environmental toxicants and autism spectrum disorders: a systematic review. Transl Psychiatry 2014; 4: e360. 10.1038/tp.2014.4

[12]

Lanni KE, Schupp CW, Simon D, Corbett BA . Verbal ability, social stress, and anxiety in children with autistic disorder. Autism 2012; 16: 123–138. 10.1177/1362361311425916

[13]

Theoharides TC, Weinkauf C, Conti P . Brain cytokines and neuropsychiatric disorders. J Clin Psychopharmacol 2004; 24: 577–581. 10.1097/01.jcp.0000148026.86483.4f

[14]

Buie T, Campbell DB, Fuchs GJ III, Furuta GT, Levy J, Vandewater J et al. Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report. Pediatrics 2010; 125: S1–18. 10.1542/peds.2009-1878c

[15]

Rossignol DA, Frye RE . Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol Psychiatry 2012; 17: 290–314. 10.1038/mp.2010.136

[16]

Angelidou A, Alysandratos KD, Asadi S, Zhang B, Francis K, Vasiadi M et al. Brief report: ‘allergic symptoms’ in children with autism spectrum disorders. More than meets the eye? J Autism Dev Disord 2011; 41: 1579–1585. 10.1007/s10803-010-1171-z

[17]

Gurney JG, McPheeters ML, Davis MM . Parental report of health conditions and health care use among children with and without autism: National Survey of Children's Health. Arch Pediatr Adolesc Med 2006; 160: 825–830. 10.1001/archpedi.160.8.825

[18]

Theoharides TC, Zhang B . Neuro-Inflammation, blood-brain barrier, seizures and autism. J Neuroinflamm 2011; 8: 168. 10.1186/1742-2094-8-168

[19]

Hagberg H, Gressens P, Mallard C . Inflammation during fetal and neonatal life: implications for neurologic and neuropsychiatric disease in children and adults. Ann Neurol 2012; 71: 444–457. 10.1002/ana.22620

[20]

Gupta S, Ellis SE, Ashar FN, Moes A, Bader JS, Zhan J et al. Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism. Nat Commun 2014; 5: 5748. 10.1038/ncomms6748

[21]

Skaper SD, Facci L, Giusti P . Mast cells, glia and neuroinflammation: partners in crime? Immunology 2014; 141: 314–327. 10.1111/imm.12170

[22]

Theoharides TC, Singh LK, Boucher W, Pang X, Letourneau R, Webster E et al. Corticotropin-releasing hormone induces skin mast cell degranulation and increased vascular permeability, a possible explanation for its pro-inflammatory effects. Endocrinology 1998; 139: 403–413. 10.1210/endo.139.1.5660

[23]

Theoharides TC . Autism spectrum disorders and mastocytosis. Int J Immunopathol Pharmacol 2009; 22: 859–865. 10.1177/039463200902200401

[24]

Mast Cells, Mastocytosis, and Related Disorders

THEOHARIS C. THEOHARIDES, Peter Valent, Cem Akin

New England Journal of Medicine 2015 10.1056/nejmra1409760

[25]

Angelidou A, Francis K, Vasiadi M, Alysandratos K-D, Zhang B, Theoharides A et al. Neurotensin is increased in serum of young children with autistic disorder. J Neuroinflamm 2010; 7: 48. 10.1186/1742-2094-7-48

[26]

Carraway R, Leeman SE . The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalami. J Biol Chem 1973; 248: 6854–6861. 10.1016/s0021-9258(19)43429-7

[27]

Mustain WC, Rychahou PG, Evers BM . The role of neurotensin in physiologic and pathologic processes. Curr Opin Endocrinol Diabetes Obes 2011; 18: 75–82. 10.1097/med.0b013e3283419052

[28]

Tsilioni I, Dodman N, Petra AI, Taliou A, Francis K, Moon-Fanelli AA et al. Elevated serum neurotensin and CRH levels in children with autistic spectrum disorders and tail-chasing bull terriers with a phenotype similar to autism. Transl Psychiatry 2014; 4: e466. 10.1038/tp.2014.106

[29]

Donelan J, Boucher W, Papadopoulou N, Lytinas M, Papaliodis D, Theoharides TC . Corticotropin-releasing hormone induces skin vascular permeability through a neurotensin-dependent process. Proc Natl Acad Sci USA 2006; 103: 7759–7764. 10.1073/pnas.0602210103

[30]

Theoharides TC, Stewart JM, Panagiotidou S, Melamed I . Mast cells, brain inflammation and autism. Eur J Pharmacol 2015 pii: S0014-2999(15)00398-2.

[31]

Kritas SK, Saggini A, Cerulli G, Caraffa A, Antinolfi P, Pantalone A et al. Corticotropin-releasing hormone, microglia and mental disorders. Int J Immunopathol Pharmacol 2014; 27: 163–167. 10.1177/039463201402700203

[32]

Theoharides TC . Is a subtype of autism an ‘allergy of the brain’? Clin Ther 2013; 35: 584–591. 10.1016/j.clinthera.2013.04.009

[33]

Theoharides TC, Angelidou A, Alysandratos KD, Zhang B, Asadi S, Francis K et al. Mast cell activation and autism. Biochim Biophys Acta 2012; 1822: 34–41. 10.1016/j.bbadis.2010.12.017

[34]

The Effects of Plant Flavonoids on Mammalian Cells:Implications for Inflammation, Heart Disease, and Cancer

Elliott Middleton, Chithan Kandaswami, THEOHARIS C. THEOHARIDES

Pharmacological Reviews 2000 10.1016/s0031-6997(24)01472-8

[35]

Weng Z, Patel A, Panagiotidou S, Theoharidess TC . The novel flavone tetramethoxyluteolin is a potent inhibitor of human mast cells. J Allergy Clin Immunol 2014; 14: 1044–1052.

[36]

Kempuraj D, Madhappan B, Christodoulou S, Boucher W, Cao J, Papadopoulou N et al. Flavonols inhibit proinflammatory mediator release, intracellular calcium ion levels and protein kinase C theta phosphorylation in human mast cells. Br J Pharmacol 2005; 145: 934–944. 10.1038/sj.bjp.0706246

[37]

Park HH, Lee S, Son HY, Park SB, Kim MS, Choi EJ et al. Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells. Arch Pharm Res 2008; 31: 1303–1311. 10.1007/s12272-001-2110-5

[38]

Kimata M, Shichijo M, Miura T, Serizawa I, Inagaki N, Nagai H . Effects of luteolin, quercetin and baicalein on immunoglobulin E-mediated mediator release from human cultured mast cells. Clin Exp Allergy 2000; 30: 501–508. 10.1046/j.1365-2222.2000.00768.x

[39]

Kritas SK, Saggini A, Varvara G, Murmura G, Caraffa A, Antinolfi P et al. Luteolin inhibits mast cell-mediated allergic inflammation. J Biol Regul Homeost Agents 2013; 27: 955–959.

[40]

Jang S, Kelley KW, Johnson RW . Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1. Proc Natl Acad Sci USA 2008; 105: 7534–7539. 10.1073/pnas.0802865105

[41]

Parker-Athill E, Luo D, Bailey A, Giunta B, Tian J, Shytle RD et al. Flavonoids, a prenatal prophylaxis via targeting JAK2/STAT3 signaling to oppose IL-6/MIA associated autism. J Neuroimmunol 2009; 217: 20–27. 10.1016/j.jneuroim.2009.08.012

[42]

Kempuraj D, Tagen M, Iliopoulou BP, Clemons A, Vasiadi M, Boucher W et al. Luteolin inhibits myelin basic protein-induced human mast cell activation and mast cell dependent stimulation of Jurkat T cells. Br J Pharmacol 2008; 155: 1076–1084. 10.1038/bjp.2008.356

[43]

Chen HQ, Jin ZY, Wang XJ, Xu XM, Deng L, Zhao JW . Luteolin protects dopaminergic neurons from inflammation-induced injury through inhibition of microglial activation. Neurosci Lett 2008; 448: 175–179. 10.1016/j.neulet.2008.10.046

[44]

Sharma V, Mishra M, Ghosh S, Tewari R, Basu A, Seth P et al. Modulation of interleukin-1beta mediated inflammatory response in human astrocytes by flavonoids: implications in neuroprotection. Brain Res Bull 2007; 73: 55–63. 10.1016/j.brainresbull.2007.01.016

[45]

Luteolin triggers global changes in the microglial transcriptome leading to a unique anti-inflammatory and neuroprotective phenotype

Konstantin Dirscherl, Marcus Karlstetter, Stefanie Ebert et al.

Journal of Neuroinflammation 2010 10.1186/1742-2094-7-3

[46]

Jang S, Dilger RN, Johnson RW . Luteolin inhibits microglia and alters hippocampal-dependent spatial working memory in aged mice. J Nutr 2010; 140: 1892–1898. 10.3945/jn.110.123273

[47]

Kao TK, Ou YC, Lin SY, Pan HC, Song PJ, Raung SL et al. Luteolin inhibits cytokine expression in endotoxin/cytokine-stimulated microglia. J Nutr Biochem 2011; 22: 612–624. 10.1016/j.jnutbio.2010.01.011

[48]

Asadi S, Zhang B, Weng Z, Angelidou A, Kempuraj D, Alysandratos KD et al. Luteolin and thiosalicylate inhibit HgCl(2) and thimerosal-induced VEGF release from human mast cells. Int J Immunopathol Pharmacol 2010; 23: 1015–1020. 10.1177/039463201002300406

[49]

Franco JL, Posser T, Missau F, Pizzolatti MG, Dos Santos AR, Souza DO et al. Structure-activity relationship of flavonoids derived from medicinal plants in preventing methylmercury-induced mitochondrial dysfunction. Environ Toxicol Pharmacol 2010; 30: 272–278. 10.1016/j.etap.2010.07.003

[50]

Taliou A, Zintzaras E, Lykouras L, Francis K . An open-label pilot study of a formulation containing the anti-inflammatory flavonoid luteolin and its effects on behavior in children with autism spectrum disorders. Clin Ther 2013; 35: 592–602. 10.1016/j.clinthera.2013.04.006

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Published: Sep 29, 2015
Vol/Issue: 5(9)
Pages: e647-e647
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Cite This Article

I Tsilioni, A Taliou, K Francis, et al. (2015). Children with autism spectrum disorders, who improved with a luteolin-containing dietary formulation, show reduced serum levels of TNF and IL-6. Translational Psychiatry, 5(9), e647-e647. https://doi.org/10.1038/tp.2015.142

Children with autism spectrum disorders, who improved with a luteolin-containing dietary formulation, show reduced serum levels of TNF and IL-6

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