Abstract
Mannan-binding lectin-associated serine protease 1 (MASP-1), the most abundant enzyme of the complement lectin pathway, is able to stimulate human umbilical vein endothelial cells (HUVECs) to alter the expression of several cytokines and adhesion molecules. This study has assessed to what extent MASP-1 is able to modify the transcriptional pattern of inflammation-related (IR) genes in HUVECs. We utilized Agilent microarray to analyse the effects of recombinant MASP-1 (rMASP-1) in HUVECs, on a set of 884 IR genes. Gene Set Enrichment Analysis showed an overall activation of inflammation-related genes in response to rMASP-1. rMASP-1 treatment up- and down-regulated 19 and 11 IR genes, respectively. Most of them were previously unidentified, such as genes of chemokines (CXCL1, CXCL2, CXCL3), inflammatory receptors (TLR2, BDKRB2) and other inflammatory factors (F3, LBP). Expression of IR genes changed early, during the first 2 hours of activation. Both p38-MAPK inhibitor and NFκB inhibitor efficiently suppressed the effect of rMASP-1. We delineated 12 transcriptional factors as possible regulators of rMASP-1-induced IR genes. Our microarray-based data are in line with the hypothesis that complement lectin pathway activation, generating active MASP-1, directly regulates inflammatory processes by shifting the phenotype of endothelial cells towards a more pro-inflammatory type.
Highlights
The complement system, a part of the innate immune system has an indispensable role in the elimination of extracellular pathogens and necrotic/apoptotic cells
We demonstrated that the expression of E-selectin adhesion molecules in human umbilical vein endothelial cells (HUVECs) was upregulated in response to Mannan-binding lectin-associated serine protease 1 (MASP-1), which resulted in increased adherence between neutrophils and endothelial cells[3]
When analyzed recombinant MASP-1 (rMASP-1) regulated IR genes, we found that rMASP-1 treatment altered 30 out of 884 (3.39%) IR genes in HUVECs, from which 19 were up- and 11 were down-regulated (Table 1). rMASP-1 was found to regulate a diverse range of IR genes, including adhesion molecules, cytokines and growth factors, and genes involved in signal transduction (Table 1)
Summary
The complement system, a part of the innate immune system has an indispensable role in the elimination of extracellular pathogens and necrotic/apoptotic cells. Endothelium, besides having important role in the regulation of several physiological functions, participates in immunological/inflammatory processes, including leukocyte homing, antigen presentation, regulation of complement system and the clearance of immune complexes. Because of their unique anatomical localization and predisposition to inflammatory factors, the role of ECs in inflammation is crucial. The triggering factors, the localization, as well as the cellular composition of the individual inflammatory reactions are substantially different, several selective expression patterns of IR genes can be identified These ‘foot-prints’ of transcriptional patterns are known to be distinct in the case of e.g. TNFα, lipopolysaccharide (LPS) or thrombin[8,9,10,11,12], and required to an adequate response to the various provoking factors. The possible pro-inflammatory effects of MASP-1 may contribute to the pathogenesis of inflammatory diseases, where endothelium is involved, such as atherosclerosis, hereditary angioedema and sepsis
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