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DOI: 10.1055/s-0035-1562925
Inflammatory Characteristics of Monocytes from Pediatric Patients with Tuberous Sclerosis
Publikationsverlauf
23. Dezember 2014
22. Juni 2015
Publikationsdatum:
10. September 2015 (online)
Abstract
Objective Therapeutic options for the tuberous sclerosis complex (TSC) syndrome showed varying outcomes. Malfunctional tsc1/tsc2 genes leave mTOR uninhibited, a positive downstream modulator of the innate proinflammatory immune system, which has not yet been described in pediatric patients with TSC.
Methods Using polymerase chain reaction (PCR) gene expression levels of monocytes after cultivation with lipopolysaccharide (LPS) or with LPS + mTOR inhibitor rapamycin, patients with TSC (n = 16) were compared with healthy subjects (n = 20).
Results Compared with monocytes from healthy controls, LPS showed a more prominent gene expression pattern in patients with TSC (CCL24, CXCL10, IL-6, IL-10, and IL-1B). Proinflammatory reactions against LPS were modulated by rapamycin. With LPS + rapamycin monocytes from patients with TSC showed gene expression patterns different from healthy subjects. Furthermore, developmental differences were discernible in patients with TSC, compared with gene expression levels for patients 0 to 5 years to those 6 to 11 years of age, the latter with marked expression of IL-6 IL-1A, IL-1B, RIPK2, but also IL-10.
Conclusion The effects of LPS, even more of LPS with rapamycin on monocytes from patients with TSC suggested that inflammatory processes are distinct from those in healthy subjects. Furthermore, reaction to rapamycin indicates age-related gene expression levels. Our findings offer a model to decipher the unknown and varying gene expression pattern induced by rapamycin.
Supplementary Data
Supplementary data (Figs. S1 and S2, and Table S1) are available at: www.thieme-connect.com/products/ejournals/html/10.1055/s-0035-1562925.
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References
- 1 Krueger DA, Northrup H. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013; 49 (4) 255-265
- 2 Dazert E, Hall MN. mTOR signaling in disease. Curr Opin Cell Biol 2011; 23 (6) 744-755
- 3 Morgenstern DA, Anderson J. Inflammation: what role in pediatric cancer?. Pediatr Blood Cancer 2012; 58 (5) 659-664
- 4 Jülich K, Sahin M. Mechanism-based treatment in tuberous sclerosis complex. Pediatr Neurol 2014; 50 (4) 230-236
- 5 Cardamone M, Flanagan D, Mowat D, Kennedy SE, Chopra M, Lawson JA. Mammalian target of rapamycin inhibitors for intractable epilepsy and subependymal giant cell astrocytomas in tuberous sclerosis complex. J Pediatr 2014; 164 (5) 1195-1200
- 6 Krueger DA, Care MM, Holland K , et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 2010; 363 (19) 1801-1811
- 7 Yang H, Wang X, Zhang Y , et al. Modulation of TSC-mTOR signaling on immune cells in immunity and autoimmunity. J Cell Physiol 2014; 229 (1) 17-26
- 8 Crino PB. Evolving neurobiology of tuberous sclerosis complex. Acta Neuropathol 2013; 125 (3) 317-332
- 9 Salmond RJ, Zamoyska R. The influence of mTOR on T helper cell differentiation and dendritic cell function. Eur J Immunol 2011; 41 (8) 2137-2141
- 10 Thomson AW, Turnquist HR, Raimondi G. Immunoregulatory functions of mTOR inhibition. Nat Rev Immunol 2009; 9 (5) 324-337
- 11 Ashhurst TM, van Vreden C, Niewold P, King NJC. The plasticity of inflammatory monocyte responses to the inflamed central nervous system. Cell Immunol 2014; 291 (1–2) 49-57
- 12 Zheng X, Zhang X, Kang A, Ran C, Wang G, Hao H. Thinking outside the brain for cognitive improvement: Is peripheral immunomodulation on the way?. Neuropharmacology 2015; 96: 94-104
- 13 Schmitz F, Heit A, Dreher S , et al. Mammalian target of rapamycin (mTOR) orchestrates the defense program of innate immune cells. Eur J Immunol 2008; 38 (11) 2981-2992
- 14 Lee D-F, Hung M-C. All roads lead to mTOR: integrating inflammation and tumor angiogenesis. Cell Cycle 2007; 6 (24) 3011-3014
- 15 Schaeffer V, Arbabi S, Garcia IA , et al. Role of the mTOR pathway in LPS-activated monocytes: influence of hypertonic saline. J Surg Res 2011; 171 (2) 769-776
- 16 Rossol M, Heine H, Meusch U , et al. LPS-induced cytokine production in human monocytes and macrophages. Crit Rev Immunol 2011; 31 (5) 379-446
- 17 Chen C, Khismatullin DB. Lipopolysaccharide induces the interactions of breast cancer and endothelial cells via activated monocytes. Cancer Lett 2014; 345 (1) 75-84
- 18 Wu X, Reddy DS. Integrins as receptor targets for neurological disorders. Pharmacol Ther 2012; 134 (1) 68-81
- 19 Sabat R. IL-10 family of cytokines. Cytokine Growth Factor Rev 2010; 21 (5) 315-324
- 20 Basha S, Surendran N, Pichichero M. Immune responses in neonates. Expert Rev Clin Immunol 2014; 10 (9) 1171-1184
- 21 Krumbiegel D, Anthogalidis-Voss C, Markus H, Zepp F, Meyer CU. Enhanced expression of IL-27 mRNA in human newborns. Pediatr Allergy Immunol 2008; 19 (6) 513-516
- 22 Procianoy RS, Silveira RC. Association between high cytokine levels with white matter injury in preterm infants with sepsis. Pediatr Crit Care Med 2012; 13 (2) 183-187
- 23 Favrais G, van de Looij Y, Fleiss B , et al. Systemic inflammation disrupts the developmental program of white matter. Ann Neurol 2011; 70 (4) 550-565
- 24 Stolp HB, Ek CJ, Johansson PA , et al. Factors involved in inflammation-induced developmental white matter damage. Neurosci Lett 2009; 451 (3) 232-236
- 25 Uludag IF, Bilgin S, Zorlu Y, Tuna G, Kirkali G. Interleukin-6, interleukin-1 beta and interleukin-1 receptor antagonist levels in epileptic seizures. Seizure 2013; 22 (6) 457-461
- 26 Ablin JN, Entin-Meer M, Aloush V , et al. Protective effect of eotaxin-2 inhibition in adjuvant-induced arthritis. Clin Exp Immunol 2010; 161 (2) 276-283
- 27 Ahmadi Z, Arababadi MK, Hassanshahi G. CXCL10 activities, biological structure, and source along with its significant role played in pathophysiology of type I diabetes mellitus. Inflammation 2013; 36 (2) 364-371
- 28 Cutler C, Antin JH. Sirolimus immunosuppression for graft-versus-host disease prophylaxis and therapy: an update. Curr Opin Hematol 2010; 17 (6) 500-504
- 29 Monti P, Mercalli A, Leone BE, Valerio DC, Allavena P, Piemonti L. Rapamycin impairs antigen uptake of human dendritic cells. Transplantation 2003; 75 (1) 137-145
- 30 Boor PPC, Metselaar HJ, Mancham S, van der Laan LJW, Kwekkeboom J. Rapamycin has suppressive and stimulatory effects on human plasmacytoid dendritic cell functions. Clin Exp Immunol 2013; 174 (3) 389-401
- 31 Li J, Kim SG, Blenis J. Rapamycin: one drug, many effects. Cell Metab 2014; 19 (3) 373-379
- 32 Waickman AT, Powell JD. Mammalian target of rapamycin integrates diverse inputs to guide the outcome of antigen recognition in T cells. J Immunol 2012; 188 (10) 4721-4729
- 33 Weichhart T, Costantino G, Poglitsch M , et al. The TSC-mTOR signaling pathway regulates the innate inflammatory response. Immunity 2008; 29 (4) 565-577
- 34 Duell BL, Tan CK, Carey AJ, Wu F, Cripps AW, Ulett GC. Recent insights into microbial triggers of interleukin-10 production in the host and the impact on infectious disease pathogenesis. FEMS Immunol Med Microbiol 2012; 64 (3) 295-313
- 35 Geissler EK. The influence of mTOR inhibitors on immunity and the relationship to post-transplant malignancy. Transp Res 2013; 2 (Suppl. 01) S2
- 36 Gasparoni A, Ciardelli L, Avanzini A , et al. Age-related changes in intracellular TH1/TH2 cytokine production, immunoproliferative T lymphocyte response and natural killer cell activity in newborns, children and adults. Biol Neonate 2003; 84 (4) 297-303
- 37 Zaghouani H, Hoeman CM, Adkins B. Neonatal immunity: faulty T-helpers and the shortcomings of dendritic cells. Trends Immunol 2009; 30 (12) 585-591