IL-11 signaling as a therapeutic target for cancer

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Date: Apr. 2015
From: Immunotherapy(Vol. 7, Issue 4)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 10,515 words
Lexile Measure: 2440L

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Author(s): Tracy L Putoczki aff1 , Matthias Ernst [*] aff1 aff2

Keywords:

cancer; GP130; IL-11; IL-6; inflammation; STAT3; therapy

Background

IL-11 is a member of the IL-6 family of cytokines, which includes IL-6, LIF, OSM, CNTF, CT-1, CLC, IL-27 and IL-31. IL-6, the family namesake, is by far the most extensively characterized cytokine of this family, despite the shared use of a common receptor subunit, GP130, among the cytokines of this family. Recently, a renewed focus on understanding the biological activities of these cytokines has revealed unique roles for individual IL-6 cytokine family members [1-4 ]. Most notably, differences have been revealed between IL-11 and IL-6, which are the only cytokines that utilize GP130 in a homodimeric complex (Figure 1), with IL-11 having unique roles during the onset and progression of various solid cancers. Here we provide an overview of our understanding of the biology of IL-11 signaling, highlighting the emerging role of IL-11 in cancer development.

Discovery & source of IL-11

IL-11 was originally discovered as a soluble factor, present in the supernatants recovered from transformed PU-34 stromal cells, which when applied to T1165 plasmacytoma cells stimulated their proliferation [ 5 ]. IL-11 was subsequently molecularly cloned from a cDNA library, that was generated from the PU-34 cell line, and predicted to encode a mature secreted protein of 178 amino acids with a molecular mass of approximately 19 kDa [ 5 ]. The corresponding genomic sequence encompasses 7 kb and comprises 5 coding exons located on chromosome 19q13.3-19q13.4 [6 ]. The crystal structure of human IL-11 reveals a typical type-1 four helix monomeric bundle, with structural features that are distinct from other IL-6 family cytokine members [7 ].

Despite its discovery over 20 years ago, little is known about the source and regulation of IL-11 expression in vivo . The 5′ region of the IL-11 gene contains numerous cis -regulatory elements, including two AP-1 motifs that are essential for TGF-[beta]1 -induced IL-11 transcriptional activation, in addition to binding sites for SP-1, STAT3, STAT5a, CTF/NF-1 and IFN/1 as well as a putative NFκB binding element [5,8 ]. Recently, post-transcriptional regulation of IL-11 has been identified following TGF-[beta]-dependent induction of the long noncoding RNA, IncRNA-ATB, interacting with IL-11 mRNA and increasing its stability [ 9 ].

Low levels of IL-11 mRNA can be detected in the murine thymus, spleen, bone, heart, lung, GI tract, kidney, brain, spinal cord, testis, uterus and ovaries [10,11 ]. We now appreciate that IL-11 is produced by many different types of cells within these organs in response to a variety of stimuli, including cytokines and respiratory viruses (Table 1). Subepithelial myofibroblasts are believed to be the most abundant cellular source of IL-11 and produce IL-11 in response to TGF-[beta], IL-1[beta] or IL-22 [12,13 ]. However, gastrointestinal epithelial cells are also a major source of secreted IL-11 [14 ]. In bronchial epithelial cells IL-17F, IL-1[beta], TGF-[beta] and retinoic acid (RA) induce IL-11 secretion [15,16 ], while in retinal pigment epithelial cells IFN-[gamma] can induce IL-11 secretion [17 ]. Other studies suggest...

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Gale Document Number: GALE|A411322518