Departments of 1 Internal Medicine, 2 Immunology, and 4 Pathology, Josephine Nefkens Institute, Erasmus MC, 3015 GD Rotterdam, The Netherlands; and 3 Radiology Department, Washington University School of Medicine, St. Louis, Missouri 63110 Submitted 3 February 2003 ; accepted in final form 6 April 2003 Increasing evidence suggests that neuropeptides play a role in the regulatory mechanisms between the neuroendocrine and immune systems. A differential expression of the five known somatostatin (SS) receptors (sst 1–5 ) has been demonstrated in human immune cells and tissues. However, little is known concerning regulation and expression of sst 1–5 and the peptide SS. Therefore, we investigated the expression and the time-dependent regulation of sst 1–5 , SS, and cortistatin (CST), a novel SS-like peptide, in human monocytes (MO), monocyte-derived macrophages (MP), and dendritic cells (DC) in the basal and lipopolysaccharide (LPS)-activated state. MO, MP, and DC selectively expressed sst 2 mRNA. SS mRNA was not detectable, whereas all samples expressed CST mRNA. Expression levels of sst 2 and CST mRNA showed marked differences and were in the rank order of MP>>DC>>>MO. LPS stimulation did not induce expression of SS or sst 1,3,4,5 . However, sst 2 mRNA expression was upregulated significantly by stimulation with LPS. CST mRNA was upregulated as well. During differentiation of MO in MP or DC, time-dependent, significantly increasing sst 2 and CST mRNA levels were found. By confocal microscopy, the presence of sst 2 receptors was demonstrated on MP, but not on DC. This study demonstrates for the first time a selective and inducible expression of the recently discovered CST, as well as sst 2 , in human monocyte-derived cells, suggesting a role for a CST-sst 2 system rather than a SS-sst 2 system in these immune cell types. cellular differentiation; cellular activation; neuropeptides; messenger ribonucleic acid Address for reprint requests and other correspondence: L. J. Hofland, Dept. of Internal Medicine, Rm. Bd 240, Erasmus MC, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands (E-mail: l.hofland{at}erasmusmc.nl ).