IL-1beta-induced changes in intracellular calcium dynamics and TrpC3 expression: delineation of the signal transduction cascade

Inflammation is a key biological progress that impacts on all aspects of life. It is implicated in fertilisation, embryo development, timing of birth, protection of the living organisms from infection, brain function and ageing. Inappropriate activation of inflammatory processes underlies the development of asthma, arthritis, cardiovascular disease, premature labour and tumour formation. It is essential for scientists, therefore, to fully understand how inflammation influences organisms at the tissue and cellular level. Our project looks how inflammation is involved in priming the pregnant uterus for labour. We seek to understand how an inflammatory agent arriving at the surface of a uterine muscle cell can cause changes in deep within cells in order to switich on specific genes and thereby ultimately make the uterus muscle more capable of contracting powerfully during labour. Knowledge of this process will not only help us understand labour but give new insights into how similar muscles found in blood vessels, airways, gut and the bladder respond to inflammation. This will hopefully inform other researchers attempting to find ways to combat a wide range of diseases and promote human health.

Activation of a proinflammatory response is essential to numerous physiological processes including embryo implantation, parturition, apoptosis, proliferation, leucocyte recruitment and anticoagulation and pain modulation. Proinflammatory conditions and immune response patterns also appear to serve as a common pathway in a number of diseases including arthritis, asthma, ageing, premature labour, tumour formation and cardiovascular disease. The signal transduction pathways mediating these responses have not been clearly defined. There is, therefore, a need to fully elucidate the cellular processes activated by cytokines in the early and late phases of an inflammatory response and relate this to functional outputs. In particular, it is important to determine the impact of inflammatory mediators on intracellular calcium signals as these modulate gene expression and a wide range of cellular events and functions. Our specific interest concerns the mechanisms by which inflammation primes the uterus to contract prior to labour onset. We have previously reported the novel observation that the proinflammatory cytokine interleukin-1beta induces changes in uterine smooth muscle calcium signalling and enhanced expression of TrpC3, a protein associated with cation channel formation and calcium entry pathways activated by agonist stimulation of PtdIns(4,5)P(2) hydrolysis. The current project focuses on elucidating key signal transduction events between interleukin-1beta binding with its plasma membrane receptor and down stream activation of calcium entry pathways and enhancement of TrpC3 protein expression.