Increased levels of alternatively spliced interleukin 4 (IL-4delta2) transcripts in peripheral blood mononuclear cells from patients with systemic sclerosis.
Recent in vitro studies have shown that interleukin 4 (IL-4) induces and gamma 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 transcripts, a full-length transcript and an alternatively spliced (truncated) transcript (designated IL-4delta2), were identified in patients and normal controls. Significantly increased levels of total IL-4 transcripts (full-length plus IL-4delta2 transcripts) were found in patients with Sscl in comparison to those found in healthy controls (P = 0.003), and this increase was primarily due to an increase in the level of the alternatively spliced IL-4delta2 form. The IL-4delta2/full-length-IL-4 transcript ratio was significantly increased in Sscl patients (P < 0.0001, versus healthy controls). Sequencing analysis revealed that the frequency of IL-4 clones carrying the IL-4delta2 transcript was also substantially increased in patients with Sscl. 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 transcript levels. The up-regulation of the fibrogenic IL-4 (a TH2 cytokine) in Sscl suggests a pathogenic role for IL-4 in this disease.
Sakkas
L I
LI
Department of Microbiology and Immunology, Department of Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Tourtellotte
C
C
Berney
S
S
Myers
A R
AR
Platsoucas
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CD
D000328:Adult; D017398:Alternative Splicing / Q000276:immunology*; D003001:Cloning, Molecular; D005260:Female; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics* / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012595:Scleroderma, Systemic / Q000209:etiology / Q000235:genetics* / Q000276:immunology*; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic / Q000276:immunology
D012333:RNA, Messenger; D015847:Interleukin-4; D007371:Interferon-gamma