Date on Master's Thesis/Doctoral Dissertation

8-2012

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Physiology and Biophysics

Committee Chair

Polk, Hiram Carey

Author's Keywords

Inflammation; microRNA; Sepsis; Interleukin-10; IL-10; Hypothermia; miRNA-155

Subject

Interleukins; Hypothermia; Inflammation

Abstract

This project investigated the effect of hypothermia on the monocyte response with the goal of understanding, which intracellular processes are affected by hypothermia leading to differences in cytokine secretion. A better understanding of the effects of hypothermia on the regulation of monocyte responses would allow targeted interventions and may reduce complications and death in hypothermic surgical patients. We found the following results: 1. The three major pro-inflammatory signaling pathways, Nuclear Factor Kß, p38 and c-Jun N-terminal-Kinase (JNK) of the Mitogen Activated Protein Kinases pathway, have increased and prolonged activation with hypothermia (32°C). The extracellular signal-related kinase (Erk) pathway shows increased activation at 15 minutes at 39°C. 2. The prolonged and increased activation of the pro-inflammatory signaling pathways results in a prolonged and increased expression of TNF-a messenger RNA (mRNA) and protein and microRNA-155 at 32°C. 3. Increased activation of Erk at 39°C leads to induction of Interleukin-10 mRNA and production of IL-10 protein. 4. The high IL-10 protein levels at 39°C result in suppression of the microRNA-155 expression, whereas the lack of IL-10 at 32°C prolongs microRNA-155 expression. 5. The increased and prolonged expression of microRNA-155 results in increased and prolonged TNF-a production at 32°C. The findings of our research demonstrate the importance of regulatory feedback loops in order to achieve a balanced immune response. The lack of the inhibitory IL-10 at 32°C results in a prolonged pro-inflammatory response, which may have detrimental effects on host defense with a subsequently increased susceptibility to infections and organ dysfunction. The improved understanding of the intracellular mechanisms involved in the regulation of the monocyte response may result in targeted interventions to ameliorate the detrimental effects of hypothermia.

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