Intracellular signalling pathways activated by FcgammaRI

Melendez Romero, Alirio Jose (1998) Intracellular signalling pathways activated by FcgammaRI. PhD thesis, University of Glasgow.

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The high affinity receptor for immunoglobulin G, FcgammaRI,, plays a central role in host immune defence by linking the cellular and humoral arms of the immune system. However, the signalling pathways initiated by this receptor are poorly understood. In this thesis, the intracellular signalling pathways activated by immune complexes were studied using U937 cells as a model system to investigate the effect of differentiation on these pathways. Previous work has shown that, the nature and duration of the calcium transients initiated by immune complexes in these cells changes, as the cells differentiate into cells of a more macrophage phenotype. This thesis describes the signalling pathways underlying this change. Marked differentiation dependent differences in the signalling pathways activated by immune complexes were found. Thus, in cells differentiated to a more macrophage phenotype with dbcAMP, Fc receptor aggregation resulted in the activation of PLC. In cells primed with IFN-gamma, no activation of PLC could be detected. In contrast, immune complexes in these cells resulted in the activation of PLD. The switch in the activation of intracellular signalling pathways was found to result from a switch in the use of accessory molecules by FcgammaRI. Thus, in IFN-gamma primed cells, FcgammaRI signals through the recruitment of the gamma chain whereas in dbcAMP differentiated cells FcgammaRI appears to recruit FcgammaRIIa. A novel signalling pathway responsible for calcium transients and trafficking of immune complexes to lysosomes was identified. This pathway involved the sequential activation of PLD and sphingosine kinase with the generation of sphingosine-1-phosphate. In these cytokine primed cells, immune complexes also resulted in the activation of PI3-kinase. However, an unusual pattern of PIP3 production was observed. Both forms of Class I PI3-kinase were activated. Thus, the initial peak in PIP3 resulted from the activation of the tyrosine kinase (p85) dependent form of PI3-kinase, whereas the latter, prolonged elevation of PIP3, resulted from the activation of the betagamma dependent form of PI3-kinase. The switch in signalling pathway appears to dictate the isoform of PKC activated by FcgammaRI. Thus, in cytokine primed cells where PLD is activated and the resultant calcium transients are brief, only calcium independent isoforms were activated. In dbcAMP differentiated cells, where PLC activation results in prolonged calcium signals, only the calcium dependent PKC isoforms were activated.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Janet M Allen
Keywords: Immunology
Colleges/Schools: College of Medical Veterinary and Life Sciences
Date of Award: 1998
Depositing User: Enlighten Team
Unique ID: glathesis:1998-72631
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 11 Jun 2019 11:06
Last Modified: 17 Oct 2022 14:40
Thesis DOI: 10.5525/gla.thesis.72631
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