The role of tyrosine kinases in signal transduction mechanisms utilised by human lung mast cells and basophils

Lavens-Phillips, Sandra Elizabeth (1996) The role of tyrosine kinases in signal transduction mechanisms utilised by human lung mast cells and basophils. University of Southampton, Doctoral Thesis.

Abstract

There is substantial evidence emerging which highlights a role for tyrosine kinases in IgE-mediated signalling in the rodent, however, very little is known about signalling mechanisms utilised by HLMCs and basophils. We have therefore carried out a broad spectrum pharmacological study using various inhibitors of tyrosine kinase and assessed their effects on anti-IgE induced histamine release from HLMCs and basophils. Our results indicated that non-receptor tyrosine kinases may be involved in IgE-mediated signal transduction in HLMCs and basophils. We have therefore extended these initial investigations to confirm the presence of candidate non-receptor tyrosine kinases in both cell types using SDS-PAGE and Western blotting.

The interaction of human basophils and HLMCs with the extracellular matrix is mediated by receptors on the cell surface known as integrins, in particular the VLA-4 integrin (CD29/CD49d) and signalling via these receptors is known to involve tyrosine phosphorylation. We have therefore investigated the effect of integrin clustering on HLMCs and basophils using monoclonal antibodies against either CD29 or CD49d. Our results indicate that clustering of either CD29 or CD49d failed to initiate histamine release from HLMCs and from the basophils of non-atopic and atopic donors. However, there was a significant release of histamine from the basophils of asthmatic donors which was significantly abolished in the presence of various tyrosine kinase inhibitors. These results suggest that tyrosine kinases are involved in integrin mediated signal transduction in human basophils from asthmatic donors. Clustering of the β1 integrins was also found to modulate a subsequent response to anti-IgE in both HLMCs and basophils, which was also partially reversed in the presence of various tyrosine kinase inhibitors.

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