The calcium-sensing receptor as a mediator of inflammation

Abstract

The teleologic link between increased production of pro-inflammatory cytokines resulting from a systemic inflammatory response to a burn injury and consequent stimulation of bone resorption is unclear. While it is known that cytokines can stimulate osteocytic and osteoblastic production of the ligand of the receptor activator of NFκB, or RANKL, it is not certain why this occurs. It was therefore hypothesized that the subsequent osteoclastic bone resorption liberates calcium from the bone matrix and somehow affects the inflammatory response. In this paper we show how the cytokine-mediated inflammatory response following severe burn injury in children results in simultaneous increase in bone resorption and up-regulation of the parathyroid calcium-sensing receptor. The acute bone resorption leads to release of calcium from the bone matrix with consequent calcium accumulation in the circulation. The up-regulation of the parathyroid calcium-sensing receptor suppresses the release of parathyroid hormone resulting in a lowering of blood calcium concentration. The simultaneous occurrences of these processes could regulate blood calcium concentration and if calcium concentration affects the inflammatory response, then the calcium-sensing receptor could, at the very least, modulate the inflammatory response by adjusting the blood calcium concentration. We describe in vitro studies in which we demonstrated that peripheral blood mononuclear cells in culture produce the chemokines MIP-1α and RANTES in proportion to the medium calcium concentration and they produce the chemokine MCP-1 in quantities inversely related to medium calcium concentration. CD14+monocytes in culture will also produce MIP-1α in direct relationship to medium calcium concentration but the correlation coefficient is markedly reduced compared to that with peripheral blood mononuclear cells. These monocytes, which possess the calcium-sensing receptor, do not produce MCP-1 in either direct or inverse relationship to medium calcium concentration. Therefore, it is possible that other peripheral blood mononuclear cells are primarily responsible for the production of chemokines in relation to calcium concentration but these cells have not yet been defined.

Keywords: Burns; Calcium; Calcium-sensing receptor (CaSR); Chemokines; Inflammation; Peripheral blood mononuclear cells.

Figure 1

The media concentration of the chemokine MIP-1α produced by cultured peripheral blood mononuclear cells in response to increasing media concentrations of calcium.

Figure 2

The media concentration of the chemokine RANTES produced by cultured peripheral blood mononuclear cells in response to increasing media concentrations of calcium.

Figure 3

The media concentration of the chemokine MCP-1 produced by cultured peripheral blood mononuclear cells in response to increasing media concentrations of calcium.

Figure 4

The media concentration of the chemokine MIP-1α produced by cultured CD14+ monocytes in response to increasing media concentrations of calcium.

Figure 5

A schematic diagram of metabolic alterations produced by the inflammatory and stress responses to burn injury at 24 hr post-burn and the putative roles of blood calcium concentrations and the parathyroid calcium-sensing receptor.