Background Th1 cell/cytokine repertoire contributes to systemic sclerosis (SSc) pathogenesis from early autoimmune/vascular stages while Th2 dominance prevails later, when (multi)organ fibrosis occurs . The Th1-type chemokine IFNγ-induced 10 kDa protein (CXCL10), involved in several autoimmune diseases (thyroiditis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory myopathy) exerts detrimental effects at systemic and tissue/cell level; it is reported in association with more severe SSc prognosis [2–4].
Objectives To compare circulating CXCL10 level in SSc patients starting iloprost (I), prostacyclin analogue with or without sildenafil (S), phosphodiesterase type 5 inhibitor, both vasoactive drugs used in SSc for Raynaud's phenomenon digital ischemic ulcers and/or secondary pulmonary arterial hypertension; SSc subjects under immunosuppressants (DMARDs) or corticosteroids (CCs) - first choice treatments at disease onset - before and after I were also evaluated. Intracellular path activation underlying Th1 cytokine-induced CXCL10 release by human skeletal muscle cells (Hfsmc), endothelial cells (Hfaec), cardiomyocytes (Hfcm) and fibroblasts (hFbs) were compared after iloprost or sildenafil.
Methods Sera of 27 SSc patients satisfying ACR/EULAR 2013 classification criteria for SSc were analyzed by ELISA before (T0, baseline) and 3 months after I intake (T3) vs. 15 age/gender-matched healthy subjects. Protein extracts from different human cell types were tested by Western blot for IFNγ+TNFα-induced NFkB, Stat1, JNK activation after S or I.
Results CXCL10 serum level was higher in all SSc under each drug/drug combination (range ∼300–500 pg/ml) vs. healthy subjects (∼150 pg/ml, P<0.05). I intake did not modify baseline CXCL10 in SSc subjects taking only I, DMARDs or CCs, while it significantly decreased CXCL10 in subjects under S (∼150 pg/ml, P<0.05). In Hfsmc S-induced inhibition of Stat-1/NFkB/JNK phosphorylation was higher vs. I (67/66/66% S vs. 28/30/38% I P<0.01). In Hfaec inhibition of Stat1/NFkB phosphorylation was higher and virtually prevented with I (99/92% I vs. 58/66% S P<0.01); conversely S-induced inhibition on JNK activation was significantly higher (66% S vs. 20% I P<0.01). In Hfcm I-induced inhibition was stronger on Stat1/JNK phosphorylation (67/83% I vs. 33/52% S P<0.05/P<0.01), while inhibition on NFkB was similar (70% I vs. 71% S). In hFbs, neither S nor I affected IFNγ+TNFα-induced activation of each analyzed path.
Conclusions Our in vivo results show that S and I combination is the more effective in targeting circulating CXCL10 in SSc patients. Our in vitro findings show a different inhibitory drug-induced effect onto paths underlying CXCL10 production, depending on cellular/intracellular targets. Thus, we suggest I and S combination as potential pharmacological tool in SSc not limited to treat vascular dysfunction but likely helpful to control different cell/tissue involvement and damage.
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Disclosure of Interest None declared