Date

June 2011

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Behavioral Neuroscience

Institution

Oregon Health & Science University

Abstract

Prenatal infection increases the risk of developing schizophrenia in the affected offspring, although this association is poorly understood. Animal models have demonstrated that activation of the maternal immune system produces long-term effects on the behavior in offspring that are consistent with many rodent models of schizophrenia. The identification of factors that modulate the immune response during pregnancy may guide both clinical studies and therapeutic approaches for preventive care. The overarching goal of this dissertation was to evaluate potential mediators of immune activation in response to viral infection using the synthetic viral double-stranded RNA, poly I:C. Specifically, this series of studies examines the in vitro and in vivo production of the pro-inflammatory cytokine, IL-6, in response to poly I:C. The experiments in chapter one examine the effects of poly I:C on immortalized astrocyte- and macrophage-like cells. In vitro, poly I:C exposure elicited a time- and concentration-dependent immune response in both cell lines. This included activation of the canonical inflammatory NF-κB signaling pathway and the production of IL-6. However, poly I:C did not cause inhibition of protein synthesis, although this is a common cellular response to viral infection. Chapter two examines the in vitro effects of luteolin and C16, two potential anti-inflammatory agents, on the cellular response to poly I:C. Luteolin and C16 both inhibited poly I:C-induced IL-6 protein and mRNA production, but failed to block activation of NF-κB signaling. These inhibitors also reduced protein synthesis, although they did not induce cytotoxicity. In chapter three, the effects of luteolin and C16 on poly I:C-induced IL-6 production were examined in vivo. Poly I:C elicited large increases in serum IL-6 levels in both non-pregnant and pregnant mice. In contrast to in vitro experiments, pretreatment with luteolin or C16 failed to inhibit poly I:C-induced IL-6 production. Surprisingly, pregnancy alone caused large increases in IL-6 production following poly I:C administration. Although these findings did not support an anti-inflammatory role for luteolin or C16 in response to poly I:C, they indicated that pregnancy alone may increase the inflammatory response to dsRNA. In order to further explore this pregnancy-specific effect, chapter four examines IL-6 production in mice lacking a functional TLR3. TLR3 is one of several proteins capable of binding dsRNA and initiating cytokine production. The TLR3 KO had no effect on poly I:C-induced IL-6 production in non-pregnant animals. However, in pregnant mice, the increase in poly I:C-induced IL-6 was attenuated in TLR3 KO animals. These findings indicate that inhibition of TLR3 signaling may represent a unique approach to decreasing the exaggerated inflammatory response to viral infection during pregnancy. Identification of the mechanism by which TLR3 mediates the enhanced production of IL-6 may provide insight into novel approaches for the treatment of pregnancy-specific inflammatory diseases affecting both the mother and offspring.

Identifier

doi:10.6083/M44T6GBW

School

School of Medicine

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