Dexamethasone modulates cytokine and chemokine secretion by CD4 + T cells from SSc patients and exerts antifibrotic effects in HOCl-induced SSc mice.

Abstract

The use of glucocorticoids in systemic sclerosis (SSc) is restricted due to adverse effects. Despite this, a large proportion of patients still use these medications. Their pharmacological effects on the disease are not completely known; few studies have explored them, and the results are controversial. Thus, the present study aimed to investigate the immunomodulatory and antifibrotic activity of Dexamethasone (Dex) in SSc. The effects were evaluated in CD4&#x2009;+&#x2009;T lymphocytes and macrophages from 20 SSc patients and 10 healthy volunteers and in a murine model of SSc. Cytokines (IL-4, IL-6, IL-13, IL-17A, and TNF) and chemokines (RANTES, IL-8, MIG, and IP-10) were quantified by sandwich enzyme-linked immunosorbent assay (ELISA) or cytometric bead array (CBA) in cell culture supernatant. Balb/c mice received intradermal injections of hypochlorous acid (HOCl) and treatment with Dex (1&#xa0;mg/kg) by intraperitoneal injections for 6&#xa0;weeks. RT-qPCR and histological analysis assessed dermal and pulmonary fibrosis. In the supernatant of CD4&#x2009;+&#x2009;T lymphocytes, Dex reduced the secretion of IL-4 and IL-13 (p&#x2009;<&#x2009;0.0001 for both), IL-6 (p&#x2009;=&#x2009;0.0023) and TNF (p&#x2009;=&#x2009;0.0005), in addition to the chemokines IP-10, MIG, RANTES, IL-8 (p&#x2009;<&#x2009;0.0001 for all). Furthermore, Dex treatment SSc mice significantly reduced dermal thickening (p&#x2009;<&#x2009;0.0001), mRNA expression of Col1a1 (p&#x2009;=&#x2009;0.002), Tgf&#x3b2;1 (p&#x2009;<&#x2009;0.0001) and Acta2 (p&#x2009;<&#x2009;0.0001) in the skin, and Tgf&#x3b2;1 (p&#x2009;=&#x2009;0.005) in the lungs. Furthermore, it reduced IL-4 secretion (p&#x2009;=&#x2009;0.02) in the splenocyte culture supernatant. In summary, Dex showed immunomodulatory and antifibrotic effects in SSc, evidencing its actions in treating the disease.