Interferon and alternative activation of monocyte/macrophages in systemic sclerosis-associated pulmonary arterial hypertension
Open Access
- 18 March 2011
- journal article
- systemic sclerosis
- Published by Wiley in Arthritis & Rheumatism
- Vol. 63 (6), 1718-1728
- https://doi.org/10.1002/art.30318
Abstract
Objective To explore the relationship between biomarkers of pulmonary arterial hypertension (PAH), interferon (IFN)–regulated gene expression, and the alternative activation pathway in systemic sclerosis (SSc). Methods Peripheral blood mononuclear cells (PBMCs) were purified from healthy controls, patients with idiopathic PAH, and SSc patients (classified as having diffuse cutaneous SSc, limited cutaneous SSc [lcSSc] without PAH, and lcSSc with PAH). IFN‐regulated and “PAH biomarker” genes were compared after supervised hierarchical clustering. Messenger RNA levels of selected IFN‐regulated genes (Siglec1 and MX1), biomarker genes (IL13RA1, CCR1, and JAK2), and the alternative activation marker gene (MRC1) were analyzed on PBMCs and on CD14− and CD14+ cell populations. Interleukin‐13 (IL‐13) and IL‐4 concentrations were measured in plasma by immunoassay. CD14, MRC1, and IL13RA1 surface expression was analyzed by flow cytometry. Results Increased PBMC expression of both IFN‐regulated and biomarker genes distinguished SSc patients from healthy controls. Expression of genes in the biomarker cluster, but not in the IFN‐regulated cluster, distinguished lcSSc with PAH from lcSSc without PAH. The genes CCR1 (P < 0.001) and JAK2 (P < 0.001) were expressed more highly in lcSSc patients with PAH compared with controls and mainly by CD14+ cells. MRC1 expression was increased exclusively in lcSSc patients with PAH (P < 0.001) and correlated strongly with pulmonary artery pressure (r = 0.52, P = 0.03) and higher mortality (P = 0.02). MRC1 expression was higher in CD14+ cells and was greatly increased by stimulation with IL‐13. IL‐13 concentrations in plasma were most highly increased in lcSSc patients with PAH (P < 0.001). Conclusion IFN‐regulated and biomarker genes represent distinct, although related, clusters in lcSSc patients with PAH. MRC1, a marker for the effect of IL‐13 on alternative monocyte/macrophage activation, is associated with this severe complication and is related to mortality.Keywords
This publication has 33 references indexed in Scilit:
- Limited Systemic Sclerosis Patients with Pulmonary Arterial Hypertension Show Biomarkers of Inflammation and Vascular InjuryPLOS ONE, 2010
- Type I interferon system activation and association with disease manifestations in systemic sclerosisAnnals Of The Rheumatic Diseases, 2010
- Irreversible Pulmonary Hypertension Associated with the use of Interferon Alpha for Chronic Hepatitis CDigestive Diseases and Sciences, 2010
- A four‐gene biomarker predicts skin disease in patients with diffuse cutaneous systemic sclerosisArthritis & Rheumatism, 2010
- Alternative Activation of Macrophages: An Immunologic Functional PerspectiveAnnual Review of Immunology, 2009
- Plasma cytokine profiles in systemic sclerosis: associations with autoantibody subsets and clinical manifestationsArthritis Research & Therapy, 2009
- Exploring the full spectrum of macrophage activationNature Reviews Immunology, 2008
- Interferon-inducible antiviral effectorsNature Reviews Immunology, 2008
- Identification of candidate genes in scleroderma-related pulmonary arterial hypertensionTranslational Research, 2008
- Pulmonary arterial remodeling induced by a Th2 immune responseThe Journal of Experimental Medicine, 2008