The TSC/mTOR pathway regulates the innate inflammatory response
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ABSTRACT: The TSC/mTOR (tuberous sclerosis complex/mammalian target of rapamycin) pathway has a central role in cell growth and is involved in human tumorigenesis. Here, we demonstrate an unexpected role of TSC2 and mTOR in regulating key inflammatory cytokines in monocytes, macrophages, and dendritic cells after bacterial stimulation. mTOR deficiency promoted IL-12/IL-23 and blocked IL-10 production via the transcription factor NF-kB. Conversely, loss of TSC2, a key negative regulator of mTOR, led to reduced NF-kB activity, limited IL-12 but enhanced IL-10 production. Transcriptional profiling demonstrated that mTOR additionally regulated many mediators important for inflammation and immunoregulation including PD-L1, CCR5, CCL22, and MCP-1. mTOR inhibition in vivo rescued susceptible mice from a lethal Listeria monocytogenes infection by modulating IL-12/IL-10 production. These data identify the TSC2/mTOR pathway as a novel pathway in innate immune responses by controlling NF-kB with profound clinical implications for infectious diseases, cancer, or transplantation. Keywords: inflammatory response of monocytes to LPS and rapamycin 107 CD14+ monocytes from four different donors were stimulated with 100 ng/ml LPS with or without 100 nM rapamycin for 4 hours. Cells were harvested, washed and pelleted and frozen at â80° C. Sample preparation and hybridization to a PIQORTM Immunology Microarray Human Antisense (quadrupled cDNA fragments for 1070 genes) was performed at the Miltenyi Microarray Service Unit. In brief, RNA was extracted with the TRIzol method (Sigma-Aldrich) and 1mg of total RNA was linear amplified by T7 polymerase. Total RNA from the LPS treated cells were Cy3 labeled, LPS and rapamycin treated cells were Cy5 labeled; both samples of a donor were hybridized on a single microarray. Only genes with signal intensities >2-fold above average background in one of the two channels were regarded as expressed.
ORGANISM(S): Homo sapiens
SUBMITTER: Thomas Weichhart
PROVIDER: E-GEOD-6002 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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