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J. Biol. Chem., Vol. 280, Issue 14, 14177-14188, April 8, 2005

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Calcium-sensing Receptor Gene Transcription Is Up-regulated by the Proinflammatory Cytokine, Interleukin-1

ROLE OF THE NF-B PATHWAY AND B ELEMENTS^*

Lucie Canaff and Geoffrey N. Hendy

From the Departments of Medicine, Physiology and Human Genetics, McGill University and Calcium Research Laboratory, Royal Victoria Hospital, Montreal, Quebec H3A 1A1, Canada

The calcium-sensing receptor (CASR) in parathyroid, thyroid, and kidney is essential for calcium homeostasis. Hypocalcemia is common in critically ill patients having increased circulating proinflammatory cytokines, although the causes are unknown. We hypothesized that the cytokines increase CASR expression and reduce the set point for parathyroid hormone suppression by extracellular calcium, leading to hypocalcemia and hypoparathyroidism. Here, we show in vivo in the rat that parathyroid, thyroid, and kidney CASR mRNA and protein increased after injection of interleukin-1. This was associated with decreased circulating parathyroid hormone, calcium, and 1,25-dihydroxyvitamin D levels. Interleukin-1 stimulated endogenous CASR gene transcripts and transfected promoter reporter activity in human thyroid C-cells (TT cells) and kidney proximal tubule (HKC) cells. Cotransfection of NF-B proteins enhanced activity of the reporter constructs, whereas cotransfection with inhibitor-B or application of an NF-B nuclear localization sequence peptide abrogated responsiveness to cytokine or NF-B proteins. Mutagenesis of some, but not all, of the potential B elements in the 5' part of the CASR gene led to loss of responsiveness to cytokine. These elements conferred cytokine responsiveness to a heterologous promoter, and in electrophoretic mobility shift assays, NF-B complexes formed on the same three B elements. In summary, the CASR gene has several functional B elements that mediate its upregulation by proinflammatory cytokines and probably contribute to altered extracellular calcium homeostasis in the critically ill.

Received for publication, July 28, 2004 , and in revised form, December 20, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY116081 and AY116082.

^* This work was supported by Canadian Institutes of Health Research Grant MOP-57730 and a Kidney Foundation of Canada grant (to G. N. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a Doctoral Fellowship from the Canadian Institutes of Health Research and a National Cancer Institute of Canada Research Studentship.

To whom correspondence should be addressed: Calcium Research Laboratory, Rm. H4.67, Royal Victoria Hospital, 687 Pine Ave. W., Montreal, Quebec H3A 1A1, Canada. Tel.: 514-843-1632; Fax: 514-8431712; E-mail: geoffrey.hendy{at}mcgill.ca.

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