Characterization of protein C receptor expression in monocytes

Abstract

Summary. Many sequelae associated with endotoxaemicinduced shock result from excessive production of the cytokine mediators, tumour necrosis factor alpha (TNF-a), interleukin 1 (IL-1) and IL-6 from lipopolysaccharide (LPS)-activated monocytes. Protein C (PC)/activated protein C (APC) has potent cytokine-modifying properties and is protective in animal models and human clinical trials of sepsis. The precise mechanism by which this antiinflammatory response is achieved remains unknown; however, the recently described endothelial protein C receptor (EPCR) appears to be essential for this function. The pivotal role that monocytes play in the pathophysiology of septic shock led us to investigate the possible expression of a protein C receptor on the monocyte membrane. We used similarity algorithms to screen human sequence databases for paralogues of the EPCR but found none. However, using reverse transcription±polymerase chain reaction (RT±PCR), we detected an mRNA transcribed in primary human monocytes and THP1 cells that was identical to human EPCR mRNA. We also used immunocytochemical analysis to demonstrate the expression of a protein C receptor on the surface of monocytes encoded by the same gene as EPCR. These results confirm a new member of the protein C pathway involving primary monocytes. Further characterization will be necessary to compare and contrast its biological properties with those of EPCR.

Differential regulation of matrix metalloproteinase 2 and matrix metalloproteinase 9 by activated protein C: Relevance to inflammation in rheumatoid arthritis

“…EPCR is a 46-kd type I transmembrane glycoprotein that is homologous to class I major histocompatibility complex/CD1 family of proteins (19,23). It is predominantly expressed by endothelial cells, mainly those of larger blood vessels, although recent reports have shown it to be present on some leukocytes of the innate immune system (21,42), including RA monocytes (Xue M, et al: unpublished observations). Using a blocking antibody, we have shown that EPCR is required for APC inhibition of MMP-9 in monocytes.…”

“…The conversion to APC is augmented in the presence of the specific receptor endothelial protein C receptor (EPCR) (19), which is expressed on the surface of endothelial cells, keratinocytes (20), and some leukocytes, including neutrophils and monocytes (21). In addition, APC is now recognized as playing a key role in the regulation of inflammation by down-regulating leukocyte activation and inflammatory cytokine production (22).…”

Comparison of natural and recombinant tissue factor proteins: new insights

“…It is possible that a unique lipid or a composition of lipids not related to the lipid rafts could be responsible for a high monocyte TF activity when this protein is presented in a native environment. Alternatively, a TF receptor similar to those for protein C (Galligan et al , 2001 ), factors X and Xa (McGee and Rothberger , 1986 ;Altieri et al , 1988 ;Worfolk et al , 1995 ), and the prothrombinase complex (Tracy et al , 1985 ) could be the cause of this phenomenon. Further studies are required to elucidate the nature of high monocyte TF activity.…”

Modulation of Monocyte Function by Activated Protein C, a Natural Anticoagulant

“…To date, the only known cellular receptor for activated protein C is the EPCR, a 46-kDa singlechain transmembrane glycoprotein homologous to the MHC class I/CD1 family of molecules (33). EPCR was identified originally on vascular endothelial cells and has since been detected in neutrophils (34), monocytes (34), and in the monocytic cell line THP-1 (35). Recent studies in endothelial cells suggest that the antiapoptotic effect of activated protein C is mediated by EPCR and PAR-1 and EPCR (19 -21).…”