IL-6/Stat3-driven pulmonary inflammation, but not emphysema, is dependent on interleukin-17A in mice.

Pulmonary emphysema is linked to T cell-mediated autoimmune inflammation, although the pathogenic role of specific pro-inflammatory cytokines remains unclear. The Th17 type response, characterized by the production of the cytokine interleukin (IL)-17A, is modulated in part by the IL-6/signal transducer and activator of transcription (Stat)3 signalling axis and is associated with numerous autoimmune diseases. We therefore evaluated a causal role for IL-17A in the IL-6-driven gp130(F/F) mouse model for spontaneous pulmonary inflammation and emphysema. The expression of Th17-related factors was quantified in the lungs of gp130(F/F) mice and emphysematous patients, and the degree of pulmonary inflammation and emphysema was measured in gp130(F/F)  : Il17a-/- mice by immunohistochemistry, stereology and respiratory mechanics. In gp130(F/F) mice, lung gene expression of Il17a and other Th17-related factors was augmented compared with gp130+/+ (wild-type), gp130(F/F)  : Il6-/- and gp130(F/F)  : Stat3-/+ mice displaying normalized Stat3 activity and no lung inflammation. Importantly, genetic ablation of Il17a in gp130(F/F)  : Il17a-/- mice prevented lung inflammation; however, emphysema still developed. Additionally, messenger RNA expression of inflammatory genes Cxcl1, Cxcl2, Ccl2 and Tnfα; as well as Il6 and the Stat3-target gene, Socs3, were upregulated in the lungs of gp130(F/F) mice compared with gp130(F/F)  : Il17a-/- and gp130+/+ mice. Consistent with these findings, augmented IL17A expression was observed in emphysema patients presenting with inflammation compared with inflammation-free individuals. Collectively, our data suggest that the integration of IL-17A into the IL-6/Stat3 signalling axis mediates lung inflammation, but not emphysema, and that discrete targeting of IL-17A may alleviate pulmonary inflammatory-related diseases.

Ruwanpura SM ，McLeod L ，Brooks GD ，Bozinovski S ，Vlahos R ，Longano A ，Bardin PG ，Anderson GP ，Jenkins BJ ... -  《-》

Deregulated Stat3 signaling dissociates pulmonary inflammation from emphysema in gp130 mutant mice.

Ruwanpura SM ，McLeod L ，Miller A ，Jones J ，Vlahos R ，Ramm G ，Longano A ，Bardin PG ，Bozinovski S ，Anderson GP ，Jenkins BJ ... -  《-》

The molecular pathogenesis of STAT3-driven gastric tumourigenesis in mice is independent of IL-17.

Chronic activation of the gastric mucosal adaptive immune response is a characteristic trait of gastric cancer. It has recently emerged that a new class of T helper (Th) cells, defined by their ability to produce interleukin (IL)-17A (Th17), is associated with a host of inflammatory responses, including gastritis. However, the role of these Th17 cells in the pathogenesis of gastric cancer is less clear. To formally address this, we employed gp130(F/F) mice, which spontaneously develop gastric inflammation-associated tumours akin to human intestinal-type gastric cancer. At the molecular level, these tumours demonstrate hyper-activation of the latent transcription factor signal transducer and activator of transcription (STAT)3 via the IL-6 cytokine family member, IL-11. In gp130(F/F) mice, the generation of Th17 cells, as well as the gastric expression of IL-17a and other Th17-related factors (Rorγt, IL-23), were augmented compared to wild-type gp130(+/+) mice. Consistent with a role for IL-6 and STAT3 in regulating IL-17A, increased Th17 generation and gastric expression of Th17-related factors in gp130(F/F) mice were reduced to wild-type levels in gp130(F/F) :Stat3(-/+) mice displaying normalized STAT3 activity, and also in gp130(F/F) :IL-6(-/-) mice. Importantly, genetic ablation of IL-17A in gp130(F/F) :IL-17a(-/-) mice did not suppress the initiation and growth of gastric tumours. Furthermore, IL-17A and RORC gene expression was strongly increased in human gastric biopsies from patients with gastritis, but not gastric cancer. Collectively, our data suggest that increased expression of Th17-related factors does not correlate with the molecular pathogenesis of gastric tumourigenesis.

Kennedy CL ，Najdovska M ，Jones GW ，McLeod L ，Hughes NR ，Allison C ，Ooi CH ，Tan P ，Ferrero RL ，Jones SA ，Dev A ，Sievert W ，Bhathal PS ，Jenkins BJ ... -  《-》

Interleukin-6 promotes pulmonary emphysema associated with apoptosis in mice.

Ruwanpura SM ，McLeod L ，Miller A ，Jones J ，Bozinovski S ，Vlahos R ，Ernst M ，Armes J ，Bardin PG ，Anderson GP ，Jenkins BJ ... -  《-》

Blockade of the IL-6 trans-signalling/STAT3 axis suppresses cachexia in Kras-induced lung adenocarcinoma.

Miller A ，McLeod L ，Alhayyani S ，Szczepny A ，Watkins DN ，Chen W ，Enriori P ，Ferlin W ，Ruwanpura S ，Jenkins BJ ... -  《-》