Expression of the calcium-binding proteins MRP8 and MRP14 in monocytes is regulated by a calcium-induced suppressor mechanism

Abstract

MRP8 and MRP14 are two calcium-binding proteins of the S-100 family the expression of which is restricted to distinct stages of monocytic differentiation. Heteromeric MRP8/MRP14 complexes have been shown to represent their biologically active forms. However, it is not as yet clear whether biochemical modification of complexes, or regulation on the transcriptional level, are responsible for the control of MRP8/MRP14 expression. Employing Western-blot analysis and metabolic labelling we have demonstrated that patterns and metabolism of MRP8/MRP14 complexes do not change during up- or down-regulation of MRP8/MRP14. By Northern-blot analysis it was shown that MRP8/MRP14 are regulated at the transcriptional level rather than by biochemical modification of the complexes. Elevation of intracellular calcium levels by A23187, as well as by thapsigargin, was found to lead to specific down-regulation of MRP8/MRP14 mRNA which is in contrast with data reported for inflammatory factors such as interleukin-1 or tumour necrosis factor alpha. Concomitant application of actinomycin D and calcium ionophore indicated that this suppressive effect is mediated by decreased synthesis rather than increased degradation of MRP8/MRP14 mRNA. Finally, we demonstrated that calcium-mediated down-regulation of MRP8-MRP14 can be antagonized by cycloheximide, suggesting that a calcium-induced repressor protein is responsible for suppression of MRP8-MRP14 at the transcriptional level. Our data indicate that the function of MRP8-MRP14 is restricted to events associated with early stages of myelomonocytic activation.