Blockade of IL-11 Trans-Signaling or JAK2/STAT3 Signaling Ameliorates the Profibrotic Effect of IL-11.

Abstract

OBJECTIVES:

Systemic sclerosis (SSc) is a rare rheumatic disease characterized by vascular damage, dysregulated immune response, and fibrosis. Interleukin-11 (IL-11) is upregulated in SSc. This study aimed to investigate the pathological and therapeutic role of the IL-11 trans-signaling pathway in SSc.

METHODS:

Plasma IL-11 level was evaluated in 32 patients with SSc and 15 healthy controls, while the expression levels of ADAM10, ADAM17, IL-11, IL-11 Rα, or IL-11 co-stained with CD3 or CD163 in the skin of SSc patients and healthy controls were analyzed. Fibroblasts were treated with IL-11 and ionomycin to evaluate the profibrotic effect of IL-11 trans-signaling pathway. TJ301 (sgp130Fc) and WP1066 (a JAK2/STAT3 inhibitor) intervention groups were set up to investigate the antifibrotic effect of targeting IL-11.

RESULTS:

Levels of plasma IL-11 were extremely low in most SSc patients and healthy controls. In contrast, levels of IL-11, IL-11 Rα, and ADAM10, but not ADAM17, were significantly elevated in the skin of SSc patients. Moreover, the numbers of IL-11+ CD3+ cells and IL-11+ CD163+ cells were increased in the skin of SSc patients. Besides, IL-11 and ADAM10 were also elevated in the skin and pulmonary of bleomycin-induced SSc mouse. Fibroblasts co-stimulated with IL-11 and ionomycin showed increased expression of COL3 and phosphorylation of STAT3, which could be inhibited by TJ301 or WP1066. TJ301 also ameliorated skin and lung fibrosis in BLM-induced SSc mouse.

CONCLUSIONS:

IL-11 induces fibrosis in SSc by regulating the trans-signaling pathway. Blockage of sgp130Fc or inhibition of the JAK2/STAT3 pathway could ameliorate the profibrotic effect of IL-11.

• Authors: Wenjing Ye, Qian Wang, Li Zhao, Changcheng Wang, Dandan Zhang, Mengyu Zhou, Fangfang Chen, Weiguo Wang, Zaihua Zhu, Wenyu Guo, Yun Liu, Hejian Zou, Yu Xue
• Journal: Immunological investigations (Immunol Invest) Vol. 52 Issue 6 Pg. 703-716 (Nov 2023) ISSN: 1532-4311 [Electronic] England
• PMID: 37401665 (Publication Type: Journal Article)

Chemical References

• WP1066
• Interleukin-11
• Ionomycin
• JAK2 protein, human
• Janus Kinase 2
• STAT3 protein, human
• STAT3 Transcription Factor

Topics

• Humans
• Animals
• Mice
• Interleukin-11 (adverse effects, metabolism)
• Ionomycin (adverse effects, metabolism)
• Fibrosis
• Scleroderma, Systemic (drug therapy)
• Skin (pathology)
• Signal Transduction
• Fibroblasts (pathology)
• Janus Kinase 2 (adverse effects, metabolism)
• STAT3 Transcription Factor (metabolism)