Increased levels of alternatively spliced interleukin 4 (IL-4 delta 2) transcripts in peripheral blood mononuclear cells from patients with systemic sclerosis

Recent in vitro studies have shown that interleukin 4 (IL-4) induces and ga mma interferon (IFN-gamma) inhibits collagen production. To define the TH1 (IFN-gamma) and TH2(IL-4) cytokine profiles in systemic sclerosis (Sscl), a disease characterized by widespread fibrosis, we investigated IL-4 and IFN -gamma transcripts in peripheral blood mononuclear cells and plasma protein levels in 13 patients with Sscl. Two previously identified IL-4 transcript s, a full-length transcript and an alternatively spliced (truncated) transc ript (designated IL-4 delta 2), were identified in patients and normal cont rols. Significantly increased levels of total IL-4 transcripts (full-length plus IL-4 delta 2 transcripts) were found in patients with Sscl in compari son to those found in healthy controls (P = 0.003), and this increase was p rimarily due to an increase in the level of the alternatively spliced IL-4 delta 2 form. The IL-4 delta 2/full-length-IL-4 transcript ratio was signif icantly increased in Sscl patients (P < 0.0001, versus healthy controls). S equencing analysis revealed that the frequency of IL 4 clones carrying the IL-4 delta 2 transcript was also substantially increased in patients with S scl. Plasma IL-4 protein levels were increased in Sscl patients compared to those in healthy controls (P = 0.001) and correlated with total IL-4 trans cript levels. The up-regulation of the fibrogenic IL-4 (a TH2 cytokine) in Sscl suggests a pathogenic role for IL-4 in this disease.