EXTENDED REPORT

Up regulated expression of tumour necrosis factor converting enzyme in peripheral monocytes of patients with early systemic sclerosis

T Bohgaki¹, Y Amasaki¹, N Nishimura², M Bohgaki¹, Y Yamashita¹, M Nishio¹, K-i Sawada³, S Jodo¹, T Atsumi¹, T Koike¹

¹ Department of Medicine II, Hokkaido University Graduate School of Medicine, N-15 W-7, Kita-ku, Sapporo 060-8638, Japan
² GeneticLab Co, Ltd, N-27 W-6, Kita-ku, Sapporo 001-0027, Japan
³ Department of Internal Medicine III, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan

Correspondence to:
Correspondence to:
Dr Y Amasaki
Department of Medicine II, Hokkaido University Graduate School of Medicine, Address: N-15 W-7, Kita-ku, Sapporo 060-8638, Japan; yamasaki{at}med.hokudai.ac.jp

Background: Systemic sclerosis (SSc) is accompanied by abnormalities in humoral and cellular immune systems.

Objective: To determine the genes specifically expressed in the immune system in SSc by analysis of the gene expression profile of peripheral blood mononuclear cells (PBMC) from patients with SSc, including those treated with haematopoietic stem cell transplantation (HSCT). Additionally, to investigate the clinical significance of the up regulation of tumour necrosis factor (TNF) converting enzyme (TACE).

Methods: PBMC from patients with SSc (n = 23) and other autoimmune diseases (systemic lupus erythematosus (SLE, n = 16), rheumatoid arthritis (RA, n = 29)), and from disease-free controls (n = 36) were examined. Complementary DNA arrays were used to evaluate gene expression of PBMC, in combination with real time quantitative polymerase chain reactions. TACE protein expression in PBMC was examined by fluorescence activated cell sorter (FACS).

Results: In patients with SSc 118 genes were down regulated after HSCT. Subsequent comparative analysis of SSc without HSCT and healthy controls indicated SSc-specific up regulation for three genes: monocyte chemoattractant protein-3 (p = 0.0015), macrophage inflammatory protein 3 (p = 0.0339), and TACE (p = 0.0251). In the FACS analysis, TACE protein was mainly expressed on CD14⁺ monocytes both in patients with SSc and controls. TACE expression on CD14⁺ cells was significantly increased in patients with early SSc (p = 0.0096), but not in those with chronic SSc, SLE, or RA. TACE protein levels in SSc monocytes correlated with the intracellular CD68 levels (p = 0.0016).

Conclusions: Up regulation of TACE expression was a unique profile in early SSc, and may affect the function of TNF and other immunoregulatory molecules.

Abbreviations: Ab, antibody; aCENP-B Ab, anticentromere protein-B Ab; ACR, American College of Rheumatology; ANA, antinuclear Ab; aRNP Ab, anti-ribonucleoprotein Ab; aTopo-I Ab, antitopoisomerase I Ab; CaMKIIß, calcium/calmodulin dependent protein kinase II ß; cDNA, complementary DNA; CRP, C reactive protein; CTGF, connective tissue growth factor; FACS, fluorescence activated cell sorter; FITC, fluorescein isothiocyanate; FSC, forward light scatter; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HSCT, haematopoietic stem cell transplantation; IL, interleukin; MCP, monocyte chemoattractant protein; MFI, mean fluorescence intensity; mIgG1, isotype matched control mouse IgG1; MIP, macrophage inflammatory protein; mRNA, messenger RNA; NF-B, nuclear factor-B; NIK, NF-B inducing kinase; PBMC, peripheral blood mononuclear cells; PE, phycoerythrin; RA, rheumatoid arthritis; real time PCR, quantitative TaqMan real time polymerase chain reaction; RGS, regulators of G-protein signalling; SLE, systemic lupus erythematosus; SSc, systemic sclerosis; SSC, side light scatter; TACE, tumour necrosis factor converting enzyme; TGFß, transforming growth factor ß; TNF, tumour necrosis factor ; TNF-R, TNF receptor

Keywords: systemic sclerosis; tumour necrosis factor converting enzyme (TACE); cDNA array; monocytes

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