IL‐6 Signaling during Cancer Cachexia Progression: The Female Response

Cachexia arises secondary to many chronic diseases and accounts for about 30% of cancer‐related deaths. Cachexia occurs in both sexes, but its etiology and progression have been almost exclusively examined in the male. Interleukin‐6 (IL‐6) has become an attractive therapeutic target as IL‐6 signaling is a recognized regulator of male Apc Min/+ mouse cancer cachexia progression. Despite established sex‐dependent inflammatory responses, how IL‐6 signaling contributes to female cancer cachexia progression is unknown. Consequently, we examined the role of circulating IL‐6 for female Apc Min/+ mouse cancer cachexia progression. Female Apc Min/+ mice weight and functional testing were monitored until sacrifice at 18 weeks of age. A second group of female Apc Min/+ mice underwent IL‐6 overexpression at 15 weeks of age. Blood and hindlimb muscle were collected to examine IL‐6 levels and downstream signaling. Mice were stratified into weight stable, initially cachectic, and severely cachectic groups. Plasma IL‐6 did not differ between groups (17.6 ± 6.7; 34.4 ± 18.9; 39.3 ± 13.1 pg/ml); however, muscle IL‐6 mRNA correlated with body weight loss and hindlimb muscle mass (p=0.008, 0.019). Muscle IL‐6r, gp130, and SOCS3 mRNA expression did not change with cachexia severity. Muscle STAT3 phosphorylation increased with severe cachexia compared to initial cachexia (14.8 ± 1.6 vs 5.2 ± 2.1 fold change relative to WT levels). Surprisingly, IL‐6 over‐expression did not increase muscle IL‐6 signaling or bodyweight loss. Overall, elevated IL‐6 does not exacerbate cachexia progression in the female Apc Min/+ mouse.