Serum progranulin levels are elevated in patients with systemic lupus erythematosus, reflecting disease activityReport as inadecuate




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Arthritis Research and Therapy

, 14:R244

First Online: 11 November 2012Received: 29 March 2012Revised: 15 October 2012Accepted: 09 November 2012

Abstract

IntroductionProgranulin PGRN is the precursor of granulin GRN, a soluble cofactor for toll-like receptor 9 TLR9 signaling evoked by oligonucleotide CpG-DNA. Because TLR9 signaling plays an important role in systemic lupus erythematosus SLE, we investigated whether PGRN is involved in the pathogenesis of SLE.

MethodsWe measured concentrations of serum PGRN and interleukin-6 IL-6 with enzyme-linked immunosorbent assay ELISA in patients with SLE n = 68 and in healthy controls n = 60. We assessed the correlation between the serum PGRN levels and established disease-activity indexes. The sera from the patients with high PGRN titers >80 ng-ml at the initial evaluation were reevaluated after the disease was ameliorated by treatment. We also measured the IL-6 concentration secreted by peripheral blood mononuclear cells PBMCs incubated with a oligonucleotide CpG-B in the presence or absence of recombinant human PGRN rhPGRN; and b lupus sera in the presence or absence of a neutralizing anti-PGRN antibody.

ResultsSerum PGRN levels were significantly higher in SLE patients than healthy controls. Their levels were significantly associated with activity of clinical symptoms. They also significantly correlated with values of clinical parameters, including the SLE Disease Activity Index and anti-double-stranded DNA antibody titers, and inversely with CH50, C3, and C4 levels. Moreover, serum PGRN levels significantly decreased after successful treatment of SLE. The rhPGRN significantly upregulated the production of IL-6 by PBMCs stimulated with CpG-B. Patients- sera stimulated production of IL-6 from PBMCs, which was significantly impaired by neutralization of PGRN. The serum PGRN levels significantly correlated with the serum IL-6 levels.

ConclusionsSerum PGRN could be a useful biomarker for disease activity of SLE. PGRN may be involved in the pathogenesis of SLE partly by enhancing the TLR9 signaling.

AbbreviationsACRAmerican College of Rheumatology

anti-CLanti-cardiolipin

anti-nRNPanti-ribonucleoprotein

anti-PGRN Abantibody for PGRN

anti-Roanti-Ro-SS-A

control Abisotype control antibody

CpG-ODNCpG oligonucleotide

ELISAenzyme-linked immunosorbent assay

GRNgranulin

PBMCsperipheral blood mononuclear cells

PBSphosphate-buffered saline

pDCplasmacytoid dendritic cell

PGRNprogranulin

PR3proteinase 3

RArheumatoid arthritis

rhPGRNrecombinant human PGRN

SDS-PAGEsodium dodecyl sulfate-polyacrylamide gel electrophoresis

SLEsystemic lupus erythematosus

SLEDAISLE Disease Activity Index

anti-Smanti-Smith

TLRtoll-like receptor.

Electronic supplementary materialThe online version of this article doi:10.1186-ar4087 contains supplementary material, which is available to authorized users.

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Author: Atsushi Tanaka - Hiroshi Tsukamoto - Hiroki Mitoma - Chikako Kiyohara - Naoyasu Ueda - Masahiro Ayano - Shun-ichiro Ohta -

Source: https://link.springer.com/







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