Regulation of interleukin 6 receptor expression in human monocytes and monocyte-derived macrophages. Comparison with the expression in human hepatocytes.

Abstract

IL-6 is a cytokine with pleiotropic biological functions, including induction of the hepatic acute phase response and differentiation of activated B cells into Ig-secreting plasma cells. We found that human peripheral blood monocytes express the IL-6-R, which is undetectable on the large majority of lymphocytes of healthy individuals. Stimulation of monocytes by endotoxin or IL-1 causes a rapid downregulation of IL-6-R mRNA levels and a concomitant enhancement of IL-6 mRNA expression. IL-6 itself was found to suppress the IL-6-R at high concentrations. A gradual decrease of IL-6-R mRNA levels was observed along in vitro maturation of monocytes into macrophages. We show that downregulation of IL-6-R mRNA levels by IL-1 and IL-6 is monocyte specific, since IL-6-R expression is stimulated by both IL-1 and IL-6 in cultured human primary hepatocytes. Our data indicate that under noninflammatory conditions, monocytes may play a role in binding of trace amounts of circulating IL-6. Repression of monocytic IL-6-R and stimulation of hepatocytic IL-6-R synthesis may represent a shift of the IL-6 tissue targets under inflammatory conditions.

Abnormal regulation of soluble and anchored IL-6 receptor in monocytes from patients with essential thrombocythemia

“…while the anchored receptor tended to decrease during culture in normal monocytes, as already described [34], IL-6R expression increased after 18 hours of cell culture in samples from ET patients, suggesting synthesis up-regulation. In addition, we performed monocyte culture in the presence of TAPI, a well-known inhibitor of ADAM10 and ADAM17.…”

The IL-6-Soluble IL-6Rα Autocrine Loop of Endothelial Activation as an Intermediate Between Acute and Chronic Inflammation: an Experimental Model Involving Thrombin

“…It has been suggested recently that the source of serum sIL-6R␣ could be the secretion of an alternatively spliced form by hepatocytes, whereas in situ sIL-6R␣ seems to be released by shedding of the receptors expressed on the membranes of inflammatory cells, notably neutrophils and monocytes (26,27,40). Therefore, we asked whether thrombin could act as a complete proinflammatory mediator in this model, and induce IL-6R␣ release from neutrophils, either through shedding or alternative mRNA splicing.…”

“…IL-6 functions in cells are mediated through fixation to a complex receptor, consisting in a transducing protein gp130 and a ligand protein, the IL-6R␣ (CD126) (25). Whereas gp130 is present on almost all cell types, IL-6R␣ is expressed by a limited number of cells, including hepatocytes, neutrophils, and mononuclear cells (26). However, through membrane shedding or alternative splicing, IL-6R␣ can be released by these cells into a soluble form, sIL-6R␣, that can bound IL-6 and protect it against enzyme inactivation (27)(28)(29).…”

Airway epithelial cell signaling in response to bacterial pathogens

“…61,95 Epithelial responsiveness to IL-6 is dependent upon the presence of two receptors, gp130 and IL-6Ra (gp80). 99,100 Shed soluble IL-6Ra binds to IL-6 forming a ligand-receptor complex that interacts with membrane bound gp130 in a high affinity interaction termed ''trans-signaling.'' This interaction initiates MCP-1 expression by epithelial cells which heralds the shift from acute inflammation (PMN recruitment) to a resolution phase with macrophage/monocyte signaling and clearance of apoptotic PMNs.…”