Abstract
Loss of function (LOF) in IL11RA infers IL11 signaling as important for fertility, fibrosis, inflammation and incompletely penetrant craniosynostosis. The impact of LOF in IL11 has not been characterized. We generated IL11 knockout (Il11−/−) mice that are born in expected ratios and have normal hematological profiles. Lung fibroblasts from Il11−/− mice are resistant to pro-fibrotic stimulation with TGFβ1. Following bleomycin-induced lung injury, Il11−/− mice are protected from pulmonary fibrosis and exhibit lesser ERK, STAT3 and NF-kB activation, reduced Il1b, Timp1, Ccl2 and diminished IL6 expression, both at baseline and after injury: placing Il11 activity upstream of IL6 in this model. Il11−/− female mice are infertile. Unlike Il11ra1−/− mice, Il11−/− mice do not have craniosynostosis, have normal long bone mass and reduced body weights. These data further establish the role of IL11 signaling in lung fibrosis while suggesting that bone development abnormalities can be associated with mutation of IL11RA but not IL11, which may have implications for therapeutic targeting of IL11 signaling.
Highlights
Loss of function (LOF) in IL11RA infers Interleukin 11 (IL11) signaling as important for fertility, fibrosis, inflammation and incompletely penetrant craniosynostosis
We addressed whether disruption of the IL11 locus prevented IL11 protein expression by performing ELISA on culture supernatants and found that IL11 protein was not expressed by Il11−/− lung fibroblasts at baseline or after TGFβ1 stimulation (Fig. 3E)
We provide a phenotypic description of mice with germline deletion of Il11 and explore how this relates to the phenotypes of Il11ra1-null mice, published previously
Summary
Loss of function (LOF) in IL11RA infers IL11 signaling as important for fertility, fibrosis, inflammation and incompletely penetrant craniosynostosis. Unlike Il11ra1−/− mice, Il11−/− mice do not have craniosynostosis, have normal long bone mass and reduced body weights These data further establish the role of IL11 signaling in lung fibrosis while suggesting that bone development abnormalities can be associated with mutation of IL11RA but not IL11, which may have implications for therapeutic targeting of IL11 signaling. IL11 is a member of the IL6 family of cytokines, which share the gp[130] coreceptor, but while IL6 has been studied in very great detail with an armamentarium of genetic tools to dissect its function, IL11 remains poorly c haracterised[1, 2] It is apparent from the published literature that the majority of our understanding of the biology associated with loss-of-function (LOF) in IL11 signaling is inferred from studies of IL11RA mutant humans or mice[1]. We report similarities and differences between the phenotypes of Il11−/− and Il11ra1−/− mice through direct experimentation and in comparison with the published Il11ra1−/− literature (reviewed in Ref.[1])
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