The neuropeptide vasoactive intestinal peptide: direct effects on immune cells and involvement in inflammatory and autoimmune diseases.

Neuropeptides represent an important category of endogenous contributors to the establishment and maintenance of immune deviation in the immune-privileged organs such as the CNS and in the control of acute inflammation in the peripheral immune organs. Vasoactive intestinal peptide (VIP) is a major immunoregulatory neuropeptide widely distributed in the central and peripheral nervous system. In addition to neurones, VIP is synthesized by immune cells which also express VIP receptors. Here, we review the current information on VIP production and VIP-receptor-mediated effects in the immune system, the role of endogenous and exogenous VIP in inflammatory and autoimmune disorders and the present and future VIP therapeutic approaches.

Expression of polycystin-1 enhances endoplasmic reticulum calcium uptake and decreases capacitative calcium entry in ATP-stimulated MDCK cells.

Autosomal dominant polycystic kidney disease (ADPKD) types 1 and 2 arise as a consequence of mutations in the PKD1 or PKD2 genes, encoding polycystins-1 and -2. Because loss of function of either of the polycystins leads to a very similar phenotype and the two proteins are known to interact, polycystins-1 and -2 are probably active in the same pathway. The way in which loss of either polycystin leads to the development of ADPKD remains to be established, but disturbances of cell calcium regulation are likely to play an important role. Here, we demonstrate that polycystin-1, heterologously expressed in Madin-Darby canine kidney cells, had a pronounced effect on intracellular calcium homeostasis. ATP-induced calcium responses in transfection control cells exhibited a double peak and relatively gradual return to baseline. By contrast, cells expressing heterologous polycystin-1 showed a brief, uniphasic peak and an accelerated rate of decay. Heterologously expressed polycystin-1 accelerated endoplasmic reticulum (ER) calcium reuptake and inhibited capacitative calcium entry; we found no effect of the protein on mitochondrial calcium buffering or plasma membrane calcium extrusion. We therefore propose that polycystin-1 accelerated the decay of the cell calcium response to ATP by upregulation of ER calcium reuptake and consequent minimization of the stimulus for capacitative calcium entry. It is possible that cellular dedifferentiation, fluid secretion, and proliferation might therefore arise in ADPKD as a consequence of disturbances in cytoplasmic and ER calcium homeostasis and aberrant capacitative calcium entry.