Phosphorylated STAT3 Highly Expressed in CD4+ Cells of Patients With Scleroderma

Resting T lymphocytes
Resting T lymphocytes. Coloured scanning electron micrograph (SEM) of resting T lymphocytes from a human blood sample. T lymphocytes, or T cells, are a type of white blood cell and components of the body’s immune system. They mature in the thymus. T lymphocytes recognise a specific site on the surface of pathogens or foreign objects (antigens), bind to it, and become activated to produce antibodies or cells to eliminate that antigen. Specimen courtesy of Professor Greg Towers, University College London. Magnification: x 6000 when printed at 10 centimetres wide
Researchers evaluated the phosphorylated (activated) form of STAT3 in peripheral blood mononuclear cells in patients with systemic sclerosis.

Phosphorylated signal transducer and activator of transcription 3 (pSTAT3) is highly expressed in peripheral blood mononuclear cells (PBMCs) in patients with systemic sclerosis (SSc) compared with healthy participants, according to a letter to the editor published in Rheumatology.

Recent research has indicated STAT3 overexpression in skin samples of patients with SSc, but studies investigating activation of STAT3 in the circulating immune cells of patients with SSc are lacking. The current study was designed to evaluate the phosphorylated (activated) form of STAT3 in PBMCs from patients with SSc compared with healthy participants.

A total of 40 patients with SSc who fulfilled the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria and 10 healthy participants were enrolled in the study. Researchers collected and processed the peripheral venous blood samples of all participants; additional laboratory, clinical, and instrumental assessments were conducted for patients with SSc only. Researchers used the percentage of positive cells and intensity of mean fluorescence, defined as the geometric mean of fluorescence within the gated area to calculate intracellular pSTAT3 expression. They also assessed fluorescence-activated cell-sorting results in 18 isolated PBMC samples (12 from patients with SSc), which they confirmed using Western blot analysis; total STAT3-RNA expression was evaluated by quantitative polymerase chain reaction.

Compared with PBMCs from healthy participants, flow cytometry of whole PBMCs from patients with SSc showed significantly increased intracellular pSTAT3 levels (3-fold higher; P <.0001), which researchers confirmed with Western blot analysis. When the different PBMC subsets were evaluated, the researchers detected a higher percentage and mean fluorescence intensity of pSTAT3+/CD14+ than pSTAT3+/CD4+ (P =.02) in patients with SSc compared with a negligible expression in healthy participants. Expression of pSTAT3 showed an inverse correlation with the modified Rodnan Skin Score (r=-00.37; P =.02) and body mass index (r=-0.34; P =.02), and a direct correlation with disease duration (r=0.38; P =.01). Researchers found no correlations with other SSc-related characteristics.

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Although ex vivo STAT phosphorylation could be biased because of cytokine autostimulation of PBMCs after blood draw, this possible interference could have been dampened by the huge difference in pSTAT3 expression in healthy participants and the fact that the investigators ran all experiments “on-ice.”

“These findings suggest that the phosphorylated-STAT3 analysis may aid the identification of those patients [who] could benefit from specific treatments, inhibitors of [Janus kinase (Jak)]/STAT pathways, including [IL-6] receptor antagonists. Additional studies are needed to confirm our intriguing results and to explore the specific effects of Jak/STAT3 system inhibition as a potential treatment of SSc,” the investigators concluded.


Cacciapaglia F, Perniola S, Urso L, Fornaro M, Iannone F. Phosphorylated signal transducer and activator of transcription 3 (pSTAT3) is highly expressed in CD14+ circulating cells of scleroderma patients [published online January 3, 2020]. Rheumatology (Oxford) doi:10.1093/rheumatology/kez652