This study tested the hypothesis that transcription of immediate early genes is inhibited in T cells activated in microgravity (μg). Immunosuppression during spaceflight is a major barrier to safe long-term human space habitation and travel. The goals of these experiments were to prove that μg was the cause of impaired T cell activation during spaceflight and the major mechanism for spaceflight immunosuppression as well as understand the mechanisms controlling early T cell activation. Human peripheral blood leukocytes (PBLs) from 4 different individuals were stimulated with T cell mitogen concanavalin A (ConA) and anti-CD28 onboard the International Space Station (ISS). Importantly, an onboard centrifuge was used to generate a 1g simultaneous control to isolate the effects of μg from other variables of spaceflight. Microarray expression analysis after 1.5 hours of activation demonstrated that μg- and 1g-activated T cells had distinct patterns of global gene expression and identified 47 genes that were significantly differentially down-regulated by at least 2 fold in μg. Expression of many genes involved in mitogenesis, cytokine production, apoptosis, and signal transduction and several key immediate early genes were inhibited in μg. In particular, transactivation of Rel/NFκB, CREB, and SRF gene targets were down-regulated. Expression of cREL gene targets were significantly inhibited and transcription of cREL itself was significantly reduced in μg. Analysis of gene connectivity indicated that the tumor necrosis factor (TNF) pathway is likely a major early downstream effector pathway inhibited in μg and may lead to ineffective pro-inflammatory host defenses against infectious pathogens during spaceflight. Results from these experiments indicate that μg was the causative factor for impaired T cell activation during spaceflight by inhibiting transactivation of key immediate early genes.
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|Titolo:||The Rel/NF-κB pathway and transcription of immediate early genes in T cell activation are inhibited by microgravity. J. Leucoc. Biol.|
|Data di pubblicazione:||2012|
|Appare nelle tipologie:||1.1 Articolo in rivista|