Sex differences in the relationship of IL-6 signaling to cancer cachexia progression.

Abstract

A devastating aspect of cancer cachexia is severe loss of muscle and fat mass. Though cachexia occurs in both sexes, it is not well-defined in the female. The Apc(Min/+) mouse is genetically predisposed to develop intestinal tumors; circulating IL-6 is a critical regulator of cancer cachexia in the male Apc(Min/+) mouse. The purpose of this study was to examine the relationship between IL-6 signaling and cachexia progression in the female Apc(Min/+) mouse. Male and female Apc(Min/+) mice were examined during the initiation and progression of cachexia. Another group of females had IL-6 overexpressed between 12 and 14 weeks or 15-18 weeks of age to determine whether IL-6 could induce cachexia. Cachectic female Apc(Min/+) mice lost body weight, muscle mass, and fat mass; increased muscle IL-6 mRNA expression was associated with these changes, but circulating IL-6 levels were not. Circulating IL-6 levels did not correlate with downstream signaling in muscle in the female. Muscle IL-6r mRNA expression and SOCS3 mRNA expression as well as muscle IL-6r protein and STAT3 phosphorylation increased with severe cachexia in both sexes. Muscle SOCS3 protein increased in cachectic females but decreased in cachectic males. IL-6 overexpression did not affect cachexia progression in female Apc(Min/+) mice. Our results indicate that female Apc(Min/+) mice undergo cachexia progression that is at least initially IL-6-independent. Future studies in the female will need to determine mechanisms underlying regulation of IL-6 response and cachexia induction.

• Authors: Kimbell L Hetzler, Justin P Hardee, Melissa J Puppa, Aditi A Narsale, Shuichi Sato, J Mark Davis, James A Carson
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1852 Issue 5 Pg. 816-25 (May 2015) ISSN: 0006-3002 [Print] Netherlands
• PMID: 25555992 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Adenomatous Polyposis Coli Protein
• Interleukin-6
• Receptors, Interleukin-6
• Socs3 protein, mouse
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins

Topics

• Adenomatous Polyposis Coli (blood, complications, genetics)
• Adenomatous Polyposis Coli Protein (genetics)
• Animals
• Blotting, Western
• Body Weight
• Cachexia (etiology, genetics, metabolism)
• Disease Progression
• Female
• Gene Expression
• Interleukin-6 (blood, genetics, metabolism)
• Male
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Muscle, Skeletal (metabolism, pathology)
• Organ Size
• Receptors, Interleukin-6 (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Sex Factors
• Signal Transduction
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins (genetics, metabolism)
• Time Factors