Untangling the complex web of IL-4- and IL-13-mediated signaling pathways.
ABSTRACT Unraveling the exact signaling events mediating the distinct functions of the T cell-derived cytokines interleukin-4 (IL-4) and IL-13 has been challenging because they are structurally similar and share a functional signaling receptor chain. A study now proposes a potential molecular mechanism to explain the functional differences between IL-4 and IL-13 that involves the ability of IL-4, but not IL-13, to effectively activate the insulin receptor substrate-2 (IRS-2) signaling cascade through binding to its receptor. A better understanding of the interactions of IL-4 and IL-13 with their cognate receptors may facilitate the development of therapies without unintended side effects.
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ABSTRACT: CNTO 5825 is a human anti-interleukin-13 (IL-13) monoclonal antibody (mAb) that inhibits binding of human IL-13 to IL-13Rα1 and IL-13Rα2. The purpose of this investigation was to predict human pharmacokinetics (PK) of CNTO 5825 using different allometric approaches and non-clinical PK data in order to select the right and safe doses for first-in-human (FIH) study. After intravenous (IV) administration of CNTO 5825, clearance (CL) ranged from 9.98 to 11.49 mL/day/kg in rats, and from 5.78 to 7.19 mL/day/kg in cynomolgus monkeys. The volume of distribution at steady-state (Vss) in rats was large (151.52 to 155.64 mL/kg) compared to cynomolgus monkey (49.77 to 61.10 mL/kg). The terminal half-life (T1/2 ) ranged from 12.29 to 14.15 days in rats and from 6.61 to 7.73 days in cynomolgus monkeys. The PK of CNTO 5825 was linear in 1-10 mg/kg dose range in both species. The bioavailability after subcutaneous (SC) administration was 94% and 79% in rats and cynomolgus monkeys, respectively. The predicted CL and Vss based on allometric methods and PK data from rats and monkeys were within 2-fold of observed CL and Vss in human beings; The predicted CL and Vss in human beings (70 kg) based on time-invariant method with combined PK data from rats and monkeys were 4.84 ± 1.13 mL/day/kg and 68.93 ± 35.55 mL/kg, respectively. The selected doses for the FIH study based on time-invariant method and NOAEL in toxicity studies in rats and monkeys provided exposures that were subsequently shown to be well tolerated and safe in human beings. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.Basic & Clinical Pharmacology & Toxicology 02/2015; DOI:10.1111/bcpt.12391 · 2.29 Impact Factor
Article: Cytokines in psoriasis.[Show abstract] [Hide abstract]
ABSTRACT: Psoriasis is a common inflammatory skin disease with an incompletely understood etiology. The disease is characterized by red, scaly and well-demarcated skin lesions formed by the hyperproliferation of epidermal keratinocytes. This hyperproliferation is driven by cytokines secreted by activated resident immune cells, an infiltrate of T cells, dendritic cells and cells of the innate immune system, as well as the keratinocytes themselves. Psoriasis has a strong hereditary character and has a complex genetic background. Genome-wide association studies have identified polymorphisms within or near a number of genes encoding cytokines, cytokine receptors or elements of their signal transduction pathways, further implicating these cytokines in the psoriasis pathomechanism. A considerable number of inflammatory cytokines have been shown to be elevated in lesional psoriasis skin, and the serum concentrations of a subset of these also correlate with psoriasis disease severity. The combined effects of the cytokines found in psoriasis lesions likely explain most of the clinical features of psoriasis, such as the hyperproliferation of keratinocytes, increased neovascularization and skin inflammation. Thus, understanding which cytokines play a pivotal role in the disease process can suggest potential therapeutic targets. A number of cytokines have been therapeutically targeted with success, revolutionizing treatment of this disease. Here we review a number of key cytokines implicated in the pathogenesis of psoriasis. Copyright © 2014 Elsevier Ltd. All rights reserved.Cytokine 01/2015; DOI:10.1016/j.cyto.2014.12.014 · 2.87 Impact Factor
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ABSTRACT: Radiation therapy (RT) and chemotherapy (CTX) following surgery are mainstays of treatment for breast cancer (BC). While multiple studies have recently revealed the significance of immune cells as mediators of CTX response in BC, less is known regarding roles for leukocytes as mediating outcomes following RT. To address this, we utilized a syngeneic orthotopic murine model of mammary carcinogenesis to investigate if response to RT could be improved when select immune cells or immune-based pathways in the mammary microenvironment were inhibited. Treatment of mammary tumor-bearing mice with either a neutralizing monoclonal antibody (mAb) to colony-stimulating factor-1 (CSF-1) or a small molecule inhibitor of the CSF-1 receptor kinase (i.e., PLX3397), resulting in efficient macrophage depletion, significantly delayed tumor regrowth following RT. Delayed tumor growth in this setting was associated with increased presence of CD8+ T cells, and reduced presence of CD4+ T cells, the main source of the TH2 cytokine interleukin (IL)-4 in mammary tumors. Selective depletion of CD4+ T cells or neutralization of IL-4 in combination with RT, phenocopied results following macrophage depletion, whereas depletion of CD8+ T cells abrogated improved response to RT following these therapies. Analogously, therapeutic neutralization of IL-4 or IL-13, or IL-4 receptor alpha deficiency, in combination with the CTX paclitaxel resulted in slowed primary mammary tumor growth by CD8+ T cell-dependent mechanisms. These findings indicate that clinical responses to cytotoxic therapy in general can be improved by neutralizing dominant TH2-based programs driving protumorigenic and immune suppressive pathways in mammary (breast) tumors to improve outcomes. Copyright © 2015, American Association for Cancer Research.