The Signal Transduction Pathways Involved in the Respiratory Burst of Murine Peritoneal Macrophages

Abstract

An investigation into the signalling pathways responsible for the activation of NADPH oxidase and the oxidative burst in murine peritoneal macrophages has been
conducted. An array of key enzymes and second messengers responsible for this orchestration has been identified. The ligation of complement and sugar receptors
by opsonised zymosan causes early activation of tyrosine kinases. The resultant protein tyrosine phosphorylation is crucial for the oxidative burst. Inhibition of
tyrosine phosphatase, preventing subsequent tyrosine dephosphorylation validated
this as the oxidative burst was augmented.

The phosphorylation of tyrosine residues is most likely to cause the activation of phospholipase Cy yielding inositol 1,4,5 trisphosphate (IP3) and diacylglycerol (DAG). It is very likely that it also causes activation of phosphatidylinositol 3-
kinase (PI-3K), for inhibition of this enzyme abrogates the oxidative burst. It is still obscure what the immediate downstream targets for this enzyme or its products are.
The mobilisation of intracellular calcium stores and activation of protein kinase C (PKC) are activated by IP3 and DAG respectively. NADPH oxidase activation is dependent on both of these products. Obstructing calcium mobilisation or inhibition
of PKC reduces the oxidative burst. In addition, the direct activation of PKC by phorbol myristate acetate (PMA) alone can evoke an oxidative burst, which is potentiated if calcium is raised using a calcium ionophore.

The initiation of this amplification pathway, via cell surface receptor ligation is also responsible for an influx of extracellular calcium. This is an essential prerequisite for the oxidative burst since the absence of extracellular calcium or blockade of
calcium channels inhibits it.

A ligand operated sodium channel may be involved in the opening of these voltageoperated calcium channels...

Date of Award	Nov 2000
Original language	English
Awarding Institution	Aston University