title: Calcium-sensing receptor, proinflammatory cytokines and calcium homeostasis.
abstract: The calcium-sensing receptor (CaSR) expressed in the parathyroid gland and the kidney tubule acts as the calciostat and orchestrates blood calcium homeostasis by modulating production and release of parathyroid hormone (PTH) and active vitamin D that influence Ca(2+) fluxes across the bone, kidney and intestine. Here we consider the role of the CaSR as a responder to proinflammatory cytokines released as part of the innate immune response to tissue injury and inflammation with resetting of the calciostat on the one hand and as a promoter and mediator of the initial inflammatory response on the other. The importance of the CaSR in systemic calcium homeostasis is exemplified by the fact that inactivating and activating mutations in the gene result in hypercalcemia and hypocalcemia, respectively. Proinflammatory cytokines interleukin-1β and interleukin-6 upregulate CaSR expression in parathyroid and kidney and do this through defined response elements in the CASR gene promoters. This results in decreased serum PTH and 1,25-dihydroxyvitamin D and calcium levels. This is likely to underlie the hypocalcemia that commonly occurs in critically ill patients, those with burn injury and sepsis, for example. The level of calcium in extracellular fluid bathing necrotic cells is often elevated and acts as a chemokine to attract monocytes/macrophages that express the CaSR to sites of tissue injury. Elevated levels of calcium acting via the CaSR can function as a danger signal that stimulates assembly of myeloid cell cytosolic multiprotein inflammasomes resulting in maturation of the proinflammatory cytokine IL-1β by caspase-1. Thus the CaSR is both promoter of and responder to the inflammation.
authors.affiliation: Experimental Therapeutics and Metabolism, McGill University Health Centre-Research Institute, and Departments of Medicine, Physiology and Human Genetics, McGill University, Montreal, Quebec, H4A 3J1, Canada. Electronic address: geoffrey.hendy@mcgill.ca.
authors.forename: Geoffrey N
authors.initials: GN
authors.lastname: Hendy
authors.affiliation: Experimental Therapeutics and Metabolism, McGill University Health Centre-Research Institute, and Departments of Medicine, Physiology and Human Genetics, McGill University, Montreal, Quebec, H4A 3J1, Canada.
authors.forename: Lucie
authors.initials: L
authors.lastname: Canaff
mesh_terms: D000818:Animals; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism*; D016207:Cytokines / Q000502:physiology*; D015870:Gene Expression; D006706:Homeostasis; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D044169:Receptors, Calcium-Sensing / Q000502:physiology*
chemical_list: D016207:Cytokines; D058847:Inflammasomes; D044169:Receptors, Calcium-Sensing; D002118:Calcium
keywords: Calcium-sensing receptor; Chemokine; Inflammasome; Inflammation; Interleukin-1β; Interleukin-6