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

Abstract

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.

The Proinflammatory Cytokine, Interleukin-6, Up-regulates Calcium-sensing Receptor Gene Transcription via Stat1/3 and Sp1/3

“…We showed in vivo in the rat that parathyroid, thyroid, and kidney CASR mRNA and protein increased after intraperitoneal injection of IL-1␤ (19). This was associated with decreased circulating PTH, 1,25-dihydroxyvitamin D (1,25(OH) 2 D), and calcium.…”

“…The CASR gene has two promoters (P1 and P2) yielding alternative transcripts containing either exon 1A or exon 1B 5Ј-untranslated region sequences that splice to exon 2 containing the ATG translation start codon (20 -22). We demonstrated that both the CASR gene promoters have functional B elements that mediate up-regulation by IL-1␤ (19).…”

Activity and function of the nuclear factor kappaB pathway in human parathyroid tumors

“…This observation, together with the finding that these agents significantly reduced cyclin D1 expression, provided additional evidence for the anti-proliferative role of CaR activation in parathyroid cells. The interaction between the NF-kB pathway and CaR signaling has recently been demonstrated in animal models, in which the induction of CaR expression by interleukin-1b was found to be mediated by the activation of the NF-kB pathway (Canaff & Hendy 2005).…”

Polymorphisms at the regulatory regions of the CASR gene influence stone risk in primary hyperparathyroidism

“…CASR expression in the cell membrane is controlled by two alternative promoters (P1 and P2), located before either exon 1A or exon 1B of the CASR gene. They encode the same CASR protein and their functional differences are still unknown (2)(3)(4).…”