The coxsackie-adenovirus receptor (CAR) is a viral receptor for Group B coxsackieviruses (CVB). Physiologically, CAR is a cellular adhesion protein. I report that upregulation of cardiac CAR in the young adult mouse (CAR+/MtTA+ ) caused a cardiomyopathy that was characterized by inflammation and hypertrophy. In the hearts of CAR+/MtTA+ mice c-Jun N terminal kinase (JNK) was specifically activated. JNK activation is known to promote hypertrophy of cardiomyocytes, and disrupt proteins at the intercalated disc. CVB3-infected CAR+/MtTA+ mice did not exhibit increased cardiac viral load or myocarditis severity, but did demonstrate a greater cardiac interferon-γ (IFN-γ) response when compared to littermate controls. CAR-induced expression of this antiviral cytokine may have prevented the increase in myocarditis susceptibility. Further investigation into the activation of protein kinase signaling, and antiviral signaling will provide better understanding of how CAR participates in the pathogenesis of both viral and non-viral heart diseases.

Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (leaves 95-113).

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.

Thesis (Ph. D.)--Carleton University, 2004. / Includes bibliographical references (p. 200-217). Also available in electronic format on the Internet.

Thesis (Ph. D.)--University of Washington, 2004. / Vita. Includes bibliographical references (leaves 106-122).

Stuttgart, Univ., Diss., 2002.

Thesis (Ph.D.) -- University of Texas Southwestern Medical Center at Dallas, 2006. / Embargoed. Vita. Bibliography: 180-194.

IL-1α and IL-1β are two IL-1 agonists which signals at the same receptor complex composed of IL-1R1/IL-1RAcP. However, IL-1α and IL-1β exert differential actions. A recent CNS-specific IL-1 receptor accessory protein, called IL-1RAcPb, has been characterised but its actions are unknown. In T cell line, over expression of IL-1RAcPb negatively regulate IL-1 action (Smith et al, 2009), but over-expression of IL-1RAcPb in HEK cell line induces IL-1 signaling (Lu et al, 2008). The role of IL-1RAcPb has not been studied in primary cells. The aim of this project was to investigate the role of IL-1RAcPb in IL-1-induced actions in neurones and glia, and to determine IL-1α and IL-1β differential actions in these two cell types. The role of IL-1RAcPb in IL-1-induced protein expression and IL 1α and IL-1β differential effects were investigated by treating WT and IL 1RAcPb-/- neurones and glia with IL-1α or IL-1β in the presence or absence of IL-1RA for 24 h followed by assessment of IL-6 induction by ELISA. The mechanism of IL-1RAcPb actions were studied by examining the effects of IL-1α or IL-1β on p38, ERK1/2 and Src kinase activation in neurones and glia by Western blot analysis. SB203580 (p38 inhibitor), UO126 (ERK1/2 inhibitor), and PP2 (Src kinase inhibitor) were used to determine the contribution of p38, ERK1/2 and Src kinase activation to IL-1-induced IL-6 synthesis in neuronal cultures. In WT neurones, IL-1α and IL-1β were equipotent at inducing IL-6 synthesis and p38 activation, whilst both ligands failed to induce ERK1/2 or Src kinase activation. In IL-1RAcPb-/- neurones, IL-1α and IL-1β induced similar levels of IL-6, but IL-1β was more potent than IL-1α at inducing p38 activation. IL-1α-induced p38 activation was reduced in IL-1RAcPb-/- neurones compared to WT neurones. In contrast to WT neurones, ERK1/2 was activated in IL-1RAcPb-/- neurones in response to IL-1α, whilst Src kinase was not activated by IL-1α or IL 1β. IL-1-induced IL-6 synthesis was abolished by IL-1RA, SB203580, UO126 and PP2. Interestingly PP2, a specific Src kinase inhibitor also partially inhibited basal ERK1/2 activity. In WT glial cells, IL-1α was more potent than IL-1β at inducing IL-6 synthesis but both cytokines induced ERK1/2 activation with equal potency. In IL-1RAcPb-/- glia, IL-1α and IL-1β were equally potent at inducing IL-6 synthesis and ERK1/2 activation. However, IL-α-induced-IL-6 synthesis was reduced in IL 1RAcPb-/- glia compared to WT glia. In both WT and IL-1RAcPb-/- glia, IL-1α and IL-1β induced p38 activation but not Src kinase activation . In conclusion, this study showed that in neurones, IL-1RAcPb may contribute to IL-1α-induced p38 activation but negatively regulates IL-1-induced ERK1/2 activation, therefore IL-1RAcPb may have specific effects on different signalling pathways. The effect of IL-1RAcPb could also be cell specific, as IL 1RAcPb contributed to IL-1α-induced p38 signalling in neurones but IL-6 production in glia. The role of IL-1RAcPb remains largely unknown and more investigations are required to elucidate its role in IL-1 signalling in the brain.

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