Neuropediatrics 2014; 45 - p063
DOI: 10.1055/s-0034-1390635

Effects of Rapamycin on Monocytes from Pediatric Patients with Tuberous Sclerosis

C. Meyer 1, G. Kurlemann 2, M. Sauter 3, P. Kreuzaler 4, A. Doganci 5, S. Gehring 6, C. Hertzberg 7, F. Zepp 6, M. Knuf 8
  • 1Universitätsmedizin der Johannes Gutenberg-Universität, Pädiatrische Immunologie Mainz, Mainz, Germany
  • 2Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Münster, Allgemeine Pädiatrie, Neuropädiatrie, Münster, Germany
  • 3Medizinische Klinik u. Piliklinik IV, Klinikum der Universität München, Nephrologisches Zentrum, München, Germany
  • 4Zentrum für Kinder u. Jugendmedizin des Univrsitätsklinikums Gießen, Abteilung Neuropädiatrie, Sozialpädiatrie und Epileptologie, Gießen, Germany
  • 5Zentrum für Kinder u. Jugendmedizin der Universitätsmedizin der JohGutenberg Uni Mainz, Pädiatrische Immunologie Mainz, Mainz, Germany
  • 6Zentrum für Kinder u. Jugendmedizin der Universitätsmedizin der JohGutenberg Uni Mainz, Mainz, Germany
  • 7Vivantes-Klinikum Neuköln, Behandlungszentrum Entwicklung u. Neurologie des Kindes- u. Jugendalters, Berlin, Germany
  • 8Dr. Horst-Schmidt Kliniken, Klinik für Kinder u. Jugendmedizin, Wiesbaden, Germany

Objective: Genetic defects in TSC1/TSC2 genes have been recognized as the leading cause for tuberous sclerosis (TS) complex syndrome, clinically characterized by epileptic seizures, benign brain tumors, and malformations. With defective TSC1/TSC2 gene expression the downstream factor mammalian target of rapamycin (mTOR) is activated, which is a powerful modulator of diverse cellular processes including effects on the immune system. Innate immune functions, specifically the inflammatory responses and the effects of rapamycin on monocytes in pediatric TS patients have not yet been described.

Methods: We characterized the expression levels of 84 genes related to inflammation and autoimmunity by using polymerase chain reaction array technology to assess monocytes from TS patients (n = 16) in comparison to monocytes from age-matched healthy subjects (n = 20) after in vitro overnight cultivation in the presence of lipopolysaccharides (LPS) or LPS + rapamycin.

Results: LPS induced a more vivid gene expression in monocytes from TS patients compared with healthy subjects, specifically for CCL24, CXCL10, IL-6, IL-10, and IL-1B. In the presence of LPS + rapamycin monocytes from TS patients’ gene expression pattern was clearly different from age-matched healthy subjects. In addition, age-specific differences were obvious in monocytes from TS patients, when comparing the gene expression levels for patients at age of 0 to 5 years to those 6 to 11 years, the latter group presented with significantly higher expression levels for IL-6, IL-1A, IL-1B, RIPK2, but also IL-10.

Conclusion: The detected effects of LPS, and even more those of LPS + rapamycin on monocytes from TS patients suggested, that in the absence of or with limited or defect TSC1/TSC2 gene products the processes connected to inflammation are distinct from those in monocytes from healthy subjects. We identified an age-related reaction upon application of rapamycin, which indicates a need for further investigations in the action mechanisms of rapamycin in the context of the developmental dynamic of the child organism. Our findings represent a first model to decipher these various, still unknown fields of action of rapamycin not only for monocytes, but presumably for other cell systems, including TS typical tumors.