Abstract
Jumonji Domain-Containing Protein 3 (JMJD3)/lysine demethylase 6B (KDM6B) is an epigenetic modulator that removes repressive histone marks on genes. Expression of KDM6B mRNA is elevated in leukocytes from patients with ANCA-associated vasculitis (AAV) and has been suggested to be the reason for higher proteinase 3 (PR3) mRNA expression in these cells due to derepression of PRTN3 gene transcription. MicroRNA-941 (miR-941) has been shown to target KDM6B mRNA and inhibit JMJD3 production. We therefore investigated whether polymorphonuclear granulocytes (PMNs) from patients suffering from granulomatosis with polyangiitis (GPA) have lower expression of miR-941 than healthy control donors as a biological cause for higher JMJD3 levels. We found no significant difference in the degree of maturation of PMNs from GPA patients (n = 8) and healthy controls (n = 11) as determined from cell surface expression of the neutrophil maturation marker CD16 and gene expression profile of FCGR3B. The expression of PRTN3 and KDM6B mRNAs and miR-941 was not significantly different in GPA patients and healthy controls. Transfection of pre-miR-941 into the neutrophil promyelocyte cell line PLB-985 cells did not result in reduction of the KDM6B mRNA level as shown previously in a hepatocellular carcinoma cell line. The amount of PR3 in PMNs from GPA patients and healthy controls was comparable. In conclusion, we found that PRTN3 mRNA, KDM6B mRNA, and miR-941 expression levels in PMNs do not differ between GPA patients and healthy controls, and that miR-941 does not uniformly regulate KDM6B mRNA levels by inducing degradation of the transcript. Thus, decreased miR-941 expression in PMNs cannot be part of the pathogenesis of GPA.
Highlights
Granulomatosis with polyangiitis (GPA), formerly known as Wegener’s granulomatosis, is an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV)
It was shown that the mean expression level of KDM6B mRNA is almost two-fold higher in total leukocytes from AAV patients compared to healthy controls, whilst there is an almost twentyfold increase in mean PRTN3 mRNA expression level in total leukocytes from AAV patients compared to healthy controls (HCs) [9]
Due to the variability in expression levels of miR-941, KDM6B mRNA, and PRTN3 mRNA during granulopoiesis, we decided to evaluate the stage of maturation of neutrophils from granulomatosis with polyangiitis (GPA) patients compared to healthy controls to ensure that the polymorphonuclear granulocytes (PMNs) used for comparison of RNA expression levels were of equal maturity (Table 1)
Summary
Granulomatosis with polyangiitis (GPA), formerly known as Wegener’s granulomatosis, is an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). It has been shown that there is a higher expression of the transcripts for PR3 and the epigenetic regulator JMJD3 in total leukocytes from AAV patients compared to healthy controls and it was hypothesized that removal of the inhibitory epigenetic mark H3K27me on the PRTN3 gene by JMJD3 was the reason for higher PRTN3 mRNA expression [9]. MiR-941 was shown to cause degradation of JMJD3 mRNA in an HCC cell line [10]. Based on these findings, we decided to examine whether low levels of expression of miR-941 in PMNs from GPA patients could be the reason for higher JMJD3 mRNA levels reported previously in total leukocytes from AAV patients [9]
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