Interleukin-31 and Oncostatin-M Mediate Distinct Signaling Reactions and Response Patterns in Lung Epithelial Cells

Abstract

Many mammalian cell types co-express several receptors for the evolutionarily related hematopoietic cytokines of the interleukin (IL) 4 -6 group (1). Moreover, all cell types express gp130, the common signal-transducing subunit of this receptor family. A major unresolved issue is whether the receptors for the individual IL-6 cytokines exert redundant functions because of the involvement of shared subunits, or whether they exert specific actions because of the formation of heteromeric subunit combinations. Gross analyses of cell responses to IL-6 cytokines indicated similar signaling reactions, supporting the notion of redundancy (2, 3). However, the individual receptor forms determine not only the ability of the cells to respond to specific IL-6 cytokines by mediating ligand binding but also the quantitative signaling by the relative expression levels of receptor subunits (4). The model of IL-6 cytokine receptors directing specific action takes into consideration that receptor complexes engage cytoplasmic domains of two signal-transducing subunits with distinct structures and capabilities to communicate to signaling pathways (3, 5). The ligand-dependent association of receptor subunits into signaling-competent complexes leads invariably to the activation of JAKs and to a specific pattern of auto-and trans-tyrosine phosphorylation of kinases, receptor subunits, and interacting proteins, including STATs, Src homology 2-containing phosphatase 2, Src homology 2-containing protein C (SHC) and other adaptor proteins. The receptor proximal events at the plasma membrane and the level of sustained signaling defines the duration and magnitude of cell responses, including transcriptional induction of genes, altered cell morphology, and changes in cell proliferation. Proliferation control by cytokine-activated STAT proteins has gained particular attention in part to explain the role of IL-6 cytokines in tissue damage repair (6 -8) and potential relevance to support tumorigenesis (9, 10). Unexplained thus far is the basis for the divergent outcome of IL-6 cytokine action that, in certain epithelial cell types, yields a suppression of proliferation (11), whereas in other cell types it yields a growth promotion (12, 13). Because the subunits for IL-6 cytokine receptors are encoded by single-copy genes, comparable structures and biochemical actions are expected for the receptor proteins expressed in the various cell types, regardless of the ultimate outcome of cytokine treatment.An independent assessment of receptor signaling specificity among IL-6 cytokine receptors became possible with the identification of IL-31R␣ (gp130-like protein; see Ref. 14) as a member of the IL-6R group that does not engage gp130, but OSMR␤, to form a signaling receptor complex (15,16). Based on the effects of ectopic expression in transgenic mice, IL-31, a CD4 ϩ T-cell-derived cytokine, has been associated with pruritis and dermatitis affecting dermal keratinocytes and dorsal root ganglia (17-19). Because antigenic challenge increased levels of * Th...

Alveolar Epithelial STAT3, IL-6 Family Cytokines, and Host Defense during Escherichia coli Pneumonia

“…We focused on IL-6 family members due to the importance of IL-6 during pneumonia (15,18) and the shared requisite use of the gp130/STAT signaling pathway by this family of cytokines (49). Alveolar epithelial cells express gp130 and are responsive to IL-6 family cytokines (26,47,50). Little is known about IL-6 family members other than IL-6 during pneumonia, but OSM and LIF are increased in serum and BALF of patients with pneumonia and acute lung injury (51,52).…”

Th2 Cytokines Augment IL-31/IL-31RA Interactions via STAT6-dependent IL-31RA Expression

“…IL-31 signals through a heterodimeric receptor complex of interleukin 31 receptor ␣ (IL-31RA) 3 and oncostatin M receptor ␤ (OSMR␤) subunits. IL-31 is the only known ligand for IL-31RA, which belongs to the large family of glycoprotein 130 (gp130) receptors (2).…”

“…IL-31RAv1 is homologous to human IL-31RAv4 and is expressed as a membranebound form, whereas IL-31RAv2 is a soluble form consisting of a cytokine-binding domain and fibronectin type III domains (1,2). Both the membrane-bound and soluble forms of the receptor bind to IL-31 with comparable affinity and initiate intracellular signal transduction resulting in secretion of several proinflammatory cytokines and chemokines, which play a critical role in Th2 cytokine-mediated inflammatory diseases (3,4). Although the expression and distribution of IL-31RA in different cells or tissues have not been well studied, IL-31RA is constitutively expressed by non-hematopoietic cells, such as lung epithelial cells, and also exhibits limited expression on activated monocytes and eosinophils (1,5,6).…”

IL-31 Receptor (IL-31RA) Knockout Mice Exhibit Elevated Responsiveness to Oncostatin M

“…Preliminary studies in a murine model of asthma suggest the receptor for IL-31 is upregulated after Ag sensitization and challenge in the lung (1). Stimulation of lung epithelial cell lines with IL-31 induces STAT phosphorylation and activation of the MAPK pathways p38, JNK, ERK, and Akt (8,9). Moreover, IL-31 stimulation of lung epithelium alone or in conjunction with the Th2 cytokines IL-4 and IL-13 induces the production of factors known to contribute to bronchial inflammation, tissue damage, and lung remodeling, including epidermal growth factor, vascular endothelial growth factor (VEGF), and MCP-1 (9).…”