Open Access Highly Accessed Research article

Serum progranulin levels are elevated in patients with systemic lupus erythematosus, reflecting disease activity

Atsushi Tanaka1, Hiroshi Tsukamoto1*, Hiroki Mitoma23, Chikako Kiyohara4, Naoyasu Ueda1, Masahiro Ayano1, Shun-ichiro Ohta1, Yasushi Inoue1, Yojirou Arinobu5, Hiroaki Niiro1, Takahiko Horiuchi1 and Koichi Akashi1*

Author affiliations

1 Department of Medicine and Biosystemic Science, Kyushu University, Graduate School of Medical Sciences, Fukuoka 812-8582, Japan

2 Department of Internal Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan

3 Research Fellowship Division Japan Society for the Promotion of Science, Sumitomo-Ichibancho FS Bldg., 8 Ichibancho, Chiyoda-ku, Tokyo 102-8472, Japan

4 Department of Preventive Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan

5 Center for Cellular and Molecular Medicine, Kyushu University Hospital, Fukuoka 812-8582, Japan

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Citation and License

Arthritis Research & Therapy 2012, 14:R244  doi:10.1186/ar4087

Published: 11 November 2012

Abstract

Introduction

Progranulin (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.

Methods

We 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.

Results

Serum 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.

Conclusions

Serum 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.