ABSTRACT
Interleukin (IL)-6 and IL-11 are the only canonical members of the IL-6 family of cytokines that induce signaling through a homodimer of the common ß-receptor glycoprotein (gp)130. A pre-requisite for signal transduction is the initial binding of the cytokines to their unique α-receptors, IL-6R and IL-11R. The cell-type specific expression of the two receptors determines the target cells of IL-6 and IL-11, because gp130 is ubiquitously expressed. However, ciliary neurotrophic factor (CNTF) and IL-27p28/IL-30 have been described as additional ligands for the IL-6R, underlining a remarkable plasticity among the cytokines of the IL-6 family and their receptors. In this study, we show that neither IL-6 nor IL-11 can bind to and signal through the α-receptor of the respective other cytokine. We further create eight chimeric IL-6/IL-11 receptors, which are all biologically active. We find that the domains D1 to D3, which contain the cytokine binding module (CBM), determine which cytokine can activate the chimeric receptor, whereas the stalk region, the transmembrane region, or the intracellular region do not participate in the ligand selectivity of the receptor and are therefore interchangeable between IL-6R and IL-11R. These results suggest a modular organization of the IL-6R and IL-11R, and a similar signal transduction complex of the two cytokines.
Subject(s)
Interleukin-11 Receptor alpha Subunit/chemistry , Interleukin-6 Receptor alpha Subunit/chemistry , Models, Molecular , Receptors, Interleukin-6/chemistry , Animals , Binding Sites , Cell Line , Cell Proliferation , Cytokine Receptor gp130/agonists , Cytokine Receptor gp130/chemistry , Cytokine Receptor gp130/genetics , Cytokine Receptor gp130/metabolism , Humans , Interleukin-11/genetics , Interleukin-11/metabolism , Interleukin-11 Receptor alpha Subunit/agonists , Interleukin-11 Receptor alpha Subunit/genetics , Interleukin-11 Receptor alpha Subunit/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Interleukin-6 Receptor alpha Subunit/agonists , Interleukin-6 Receptor alpha Subunit/genetics , Interleukin-6 Receptor alpha Subunit/metabolism , Ligands , Mice , Peptide Fragments/agonists , Peptide Fragments/chemistry , Peptide Fragments/genetics , Peptide Fragments/metabolism , Protein Interaction Domains and Motifs , Protein Structure, Tertiary , Protein Subunits , Receptors, Interleukin-6/agonists , Receptors, Interleukin-6/genetics , Receptors, Interleukin-6/metabolism , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism , Signal TransductionABSTRACT
Colonic dysmotility occurs in diabetes and blood plasma interleukin (IL)-6 levels are significantly elevated in type 1 diabetes mellitus. The aim of this study was to investigate whether IL-6 and the IL-6 receptor pathway mediates colonic dysfunction in type 1 diabetes mellitus. Male SD rats were treated with a single intraperitoneally injected dose of streptozotocin (STZ), and those displaying sustained high blood glucose were selected as diabetes mellitus models. Longitudinal muscle strips of colon were prepared to monitor colonic contraction in vitro. Contractile responses of strips of colon were recorded following treatment with IL-6 in control animals, and following anti IL-6 antibody treatment in STZ-induced diabetes in rats. Concentration of IL-6 in plasma and colon were determined by ELISA. Expressions of IL-6 α-receptor and IL-6 ß-receptor in colon tissues were determined by immunohistochemistry or Western blot analysis. The non-diabetes rats treated with IL-6 and the untreated diabetes rats showed increased contraction of distal colon, whereas the diabetes rats treated with anti-IL-6 antibody showed decreased contraction of distal colon compared with the untreated diabetes rats. The IL-6 levels of plasma but not colon increased in diabetes rats. The expression of IL-6 α-receptor increased in diabetes rats. These results indicate that diabetes rats show an increase in the contractions of distal colon partly via the IL-6-IL-6 receptor pathway.
