Impaired TGF-β signaling in patients with active systemic lupus erythematosus is associated with an overexpression of IL-22

• Published in: Cytokine (Philadelphia, Pa.) Vol. 108; pp. 182 - 189
• Main Authors: Rekik, Raja, Smiti Khanfir, Monia, Larbi, Thara, Zamali, Imen, Beldi-Ferchiou, Asma, Kammoun, Ons, Marzouki, Soumaya, Hamzaoui, Saloua, Mrad, Skander, Barbouche, Mohamed Ridha, Houman, Mohamed Habib, Ben Ahmed, Melika
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-08-2018; Elsevier
• Subjects: Adult; Aged; Female; Gene Expression; Human health and pathology; Humans; IL-15; IL-22; Immune Tolerance; Interleukin-15 - genetics; Interleukin-15 - immunology; Interleukin-22; Interleukins - genetics; Interleukins - immunology; Life Sciences; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - pathology; Middle Aged; Phosphorylation; Signal Transduction; Smad2 Protein - metabolism; Smad3 pathway; Systemic lupus erythematosus; T-Lymphocytes - immunology; TGF-β1; Transforming Growth Factor beta1 - immunology; Tunisia; Young Adult; Tunisia; Smad3 pathway; TGF-β1; IL-15; Systemic lupus erythematosus; IL-22
• ISSN: 1043-4666; 1096-0023
• DOI: 10.1016/j.cyto.2018.04.011

•The transcription of TGF-β target genes is impaired in CD3+ lymphocytes of active SLE patients.•The TGF-β signaling defect did not result from an impaired TGF-βRII expression or Smad2/3 phosphorylation.•The TGF-β signaling defect did not correlate with an overexpression of soluble or membrane-bound IL-15.•The impaired response to TGF-β is associated with an overexpression of IL-22 in SLE patients.
The mechanisms leading to the disruption of self-tolerance in systemic lupus erythematosus (SLE) remain elusive. Herein, we aimed to decipher the molecular basis of the impaired response of mononuclear cells to TGF-β1. The Smad3-pathway was explored on CD3+ lymphocytes in either active or non active SLE patients. An impaired transcription of TGF-β1 target genes was demonstrated in the CD3+ lymphocytes of active SLE patients confirming that the defect involves T cells and pointing to its extrinsic nature. We further demonstrate that the defect did not result from an impaired TGF-βRII expression or Smad2/3 phosphorylation suggesting that the mechanism lies downstream Smad2/3 translocation. Interestingly, the TGF-1 signaling defect did not correlate with an increased expression of soluble or membrane-bound IL-15. However, it was associated with an overexpression of IL-22. This suggests that an excessive activation of AhR pathway (through UV radiations, infections, etc.) could lead to the inhibition of immunosuppressive actions of TGF-β thus disrupting immune homeostasis in SLE. Collectively, our data suggest that the impaired response to TGF-β in SLE patients is associated with disease activity and provide new insights into the pathogenesis of SLE since it could establish the link between the environmental factors and the aberrancies of the immune system usually described in SLE.