ALD-R007

The signal transducer and activator of transcription (STAT) pathway, which regulates cell proliferation and immunity, has been implicated in chronic inflammatory diseases such as rheumatoid arthritis. However, few reports have described the effects of STAT inhibitors on endometriosis, another chronic inflammatory disease. Here, we investigated the intraperitoneal microenvironment and the effects of a STAT inhibitor in a mouse model of endometriosis. In the treatment group, a STAT3 inhibitor (Stattic®, 80 mg/kg) was orally administered three times per week; control animals received orally dosed phosphate-buffered saline. Endometriosis-like lesions and peritoneal lavage fluid were collected before and 1, 2, and 3 weeks after STAT3 inhibitor administration was initiated. The lesion area was significantly increased in both groups after the first week. However, in the treatment group, the lesion areas were significantly reduced at weeks 2 and 3 compared with week 1. Transforming growth factor (TGF)-β messenger RNA (mRNA) levels in ascites cells were significantly lower at weeks 1 and 2 than at week 0. Interleukin (IL)-6 mRNA levels were significantly higher at week 1 than at week 0 but were significantly lower at weeks 2 and 3 than at week 1. Thus, STAT inhibitors appeared to reduce the extent of endometriosis in this mouse model, and may also inhibit the IL-6 signaling pathway and reduce TGF-β levels. This study suggests that STAT inhibitors warrant further exploration for use in the treatment of endometriosis.

Keloid tissues contain inflammatory cells and upregulated pro‐inflammatory cytokines. The Janus kinase (JAK)‐signal transducer and activator of transcription (STAT) pathway mediate cellular responses to these cytokines. We performed a systematic review on the role of the JAK–STAT pathway in keloid pathogenesis and the evidence for JAK–STAT inhibitors in keloid treatment. The search combined the terms (1) keloid and (2) JAK or TYK or STAT and included MeSH terms and synonyms. Two reviewers screened the articles and assessed the full texts on eligibility. Data were collected on the tested drugs and molecules, the type of cells and tissues used in the experiments, and study findings on the association between the JAK–STAT pathway and keloid cells and tissues. A total of twenty preclinical studies were included. Eleven preclinical studies proved that STAT3 expression and phosphorylation are enhanced in keloid tissue and keloid fibroblasts. Thirteen different JAK and/or STAT inhibitors were investigated. Tested drugs inhibited keloid progression as demonstrated by different processes, including reduced collagen production, cell proliferation and migration, increased cell cycle arrest and apoptosis, enhanced antioxidant responses, decreased (paracrine) signalling, and decreased profibrotic gene expression. No clinical studies have been published to date. Preclinical studies indicate a role for the JAK–STAT pathway in keloid pathogenesis and a potential role for JAK–STAT inhibitors in keloid treatment. The effect of these drugs should be further investigated on relevant biomarkers in a human keloid skin model, preferably including immune cells besides keloid fibroblasts and keratinocytes and in clinical studies.