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...
Interleukin-31 (IL-31), an IL-6 cytokine family member, is proposed to play a role in animal models of airway hyperreactivity. It is produced by activated T cells and signals via a heterodimeric receptor complex composed of IL-31Ralpha and OSMRbeta. Only low levels of IL-31Ralpha expression have been demonstrated in pulmonary epithelial cell lines, however, and little is known about the ability to regulate its expression and signaling. Therefore, primary cultures of human bronchial and alveolar epithelial cells, pulmonary fibroblasts, pulmonary macrophages, and established lines of immortalized bronchial epithelial cells (HBE) and alveolar carcinoma cells (A549) were analyzed by RT-PCR, immunoblotting, and thymidine incorporation. Distinct, cell type-specific regulation of IL-31Ralpha expression was detected. Transforming growth factor-beta (TGF-beta) enhanced IL-31Ralpha mRNA expression in primary cultures and established lines of epithelial cells, but not in macrophages. In contrast, interferon-gamma (IFN-gamma) induced IL-31Ralpha mRNA expression in macrophages. IL-31Ralpha protein expression was below detection threshold in primary epithelial cell cultures but was detectable in A549 cells and increased with TGF-beta treatment. In HBE and A549 cells, TGF-beta pretreatment increased IL-31-mediated Stat3 and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. In A549 cells, TGF-beta magnified IL-31-dependent suppression of proliferation. The data suggest that increased IL-31Ralpha expression correlates with an enhanced response to IL-31.
Psoriasis is a T-cell-mediated autoimmune disease involving the skin. Two cytokines, interleukin-12 (IL-12) and IL-23 have been shown to play a pivotal role in the pathogenesis of the disease. Ustekinumab (Stelara) is a therapeutic monoclonal antibody (mAb) targeted against the p40 shared subunit of . Recently the ability of therapeutic proteins (TP) including mAbs that target either cytokines directly (e.g., Pegasys; peginterferon a-2a) or their respective cell surface receptors [e.g., tocilizumab (Actemra); anti IL-6R] to desuppress cytochrome P450 (P450) enzymes in vitro and in the clinic, has been demonstrated. In the present study the ability of IL-12 and IL-23 to suppress multiple P450 enzymes was investigated in vitro using six separate lots of cultured human hepatocytes. Following exposure of 10 ng/ml IL-12 and IL-23 for 48 hours, either alone or in combination, no change in CYP2B6, 2C9, 2C19, or 3A4 gene expression or functional activity was observed. None of the untreated hepatocyte donors showed appreciable expression of the IL-12 or IL-23 receptors. Similar results were seen with whole human liver samples. Exposure of hepatocytes to IL-12 and/or IL-23, known P450 suppressors (IL-6 and tumor necrosis factor-a) or known P450 inducers (b-naphthoflavone, phenobarbital, and rifampicin) did not appreciably alter the expression of the IL-12 and IL-23 receptors either. Finally, in contrast to the positive control IL-6, expression of the acute phase C-reactive protein was unaltered following IL-12 and/or IL-23 treatment. Together, these data suggest a negligible propensity for IL-12 or IL-23 to directly alter P450 enzymes in human hepatocytes. IntroductionThe ability of therapeutic proteins (TP) that target cytokines to potentially mediate drug interactions through alterations in drug metabolizing enzymes is a growing concern in drug development (Huang et al., 2010). Patients with inflammatory disease often have increased circulating or local cytokine levels including interleukin-6 (IL-6), tumor necrosis factor-a (TNF-a), and interferon-gamma, which have all been shown to alter cytochrome P450 (P450) metabolic enzyme levels in the liver (Morgan, 2009). The TP treatment that neutralizes one or more of these cytokines could result in patients experiencing rebound metabolic enzyme levels, leading to decreased comedication exposure and potentially therapeutic failure. As an example, recent clinical studies by Schmitt et al., (2011) showed significantly decreased simvastatin (Zocor) exposure in rheumatoid arthritis patients receiving tocilizumab, an anti-human IL-6 receptor mAb. The decreased exposure was linked to changes in CYP3A4 expression reported by the same group following anti-IL-6R treatment in the presence and absence of tocilizumab in cultured human hepatocytes (Zhang et al., 2009).Psoriasis is a chronic inflammatory skin disease affecting approximately 2% of the population (Christophers, 2001;Nestle et al., 2009). Pathogenesis of psoriasis involves a complex interplay of various cytokines, incl...
The related members of the interleukin 6 (IL-6) family of cytokines, IL-6, leukemia inhibitory factor (LIF), and oncostatin M, act as major inflammatory mediators and induce the hepatic acute phase reaction. Normal parenchymal liver cells express the receptors for these cytokines, and these receptors activate, to a comparable level, the intracellular signaling through signal transducer and activator of transcription (
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