Abstract
Interleukin (IL)-11, a member of the IL-6 family of cytokines, exerts pleiotropic effects under normal and various disease conditions. We assessed IL-11 expression regulation and the IL-11/IL-6 ratio in osteoarthritis (OA) to better guide clinical therapeutic decision-making. Our findings suggest that Zac1, a zinc finger protein that regulates apoptosis and cell cycle arrest, is a transcription factor regulating IL-11 expression. Zac1 overexpression or knockdown respectively induced or suppressed IL-11 expression in HeLa cells. Zac1 acted synergistically with AP-1, human papillomavirus E2, and hypoxia inducible factor 1 alpha (HIF1α). IL-11 expression under various conditions, including hypoxia or treatment with phorbol 12-myristate 13-acetate or copper sulfate. Recombinant IL-11-induced phosphorylation of signal transducer and activator of transcription 3 at tyrosine 705 was reduced in a dose-dependent manner in HeLa cells. Cross-talk between Zac1, IL-11, p53, and suppressor of cytokine signaling 3 was differentially affected by copper sulfate, digoxin, and caffeine. Finally, aggressive vs. conventional treatment of OA patients was primarily determined by IL-6 levels. However, we suggest that OA patients with higher IL-11 levels may respond well to conventional treatments, even in the presence of high IL-6.
Highlights
Interleukin (IL)-11 is a member of the IL-6 family of cytokines and exerts pleiotropic effects, conferring protection in the intestine, promoting tumorigenesis in gastrointestinal, breast, and thyroid tumors, regulating macrophage differentiation, and stimulating hemopoiesis and thrombopoiesis; IL-11 regulatory mechanisms in vivo remain unclear
Our findings suggest that Zac1, a zinc finger protein that regulates apoptosis and cell cycle arrest, is a transcription factor regulating IL-11 expression
IL11 and IL-11 receptor α (IL-11Rα) were dramatically induced by Zac1 in HeLa cells (Table 2)
Summary
Interleukin (IL)-11 is a member of the IL-6 family of cytokines and exerts pleiotropic effects, conferring protection in the intestine, promoting tumorigenesis in gastrointestinal, breast, and thyroid tumors, regulating macrophage differentiation, and stimulating hemopoiesis and thrombopoiesis; IL-11 regulatory mechanisms in vivo remain unclear. While recent progress has been made toward elucidating the IL-6 and IL-11 modes of action [1,2,3,4], the effects of these molecules on certain human diseases, including osteoarthritis (OA), are not well understood. IL-11 shares characteristics with both immuneregulatory (IL-6) and neuro-protective (leukemia inhibitory factor and ciliary neurotrophic factor) members of this cytokine family. Suppressor of cytokine signaling 3 (SOCS3) limits gp130mediated signaling in a negative-feedback loop by binding to a tyrosine residue at position 757 in mice and 759 in humans [11,12,13]
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