Abstract
Interleukin (IL)-1R3 is the co-receptor in three signaling pathways that involve six cytokines of the IL-1 family (IL-1α, IL-1β, IL-33, IL-36α, IL-36β and IL-36γ). In many diseases, multiple cytokines contribute to disease pathogenesis. For example, in asthma, both IL-33 and IL-1 are of major importance, as are IL-36 and IL-1 in psoriasis. We developed a blocking monoclonal antibody (mAb) to human IL-1R3 (MAB-hR3) and demonstrate here that this antibody specifically inhibits signaling via IL-1, IL-33 and IL-36 in vitro. Also, in three distinct in vivo models of disease (crystal-induced peritonitis, allergic airway inflammation and psoriasis), we found that targeting IL-1R3 with a single mAb to mouse IL-1R3 (MAB-mR3) significantly attenuated heterogeneous cytokine-driven inflammation and disease severity. We conclude that in diseases driven by multiple cytokines, a single antagonistic agent such as a mAb to IL-1R3 is a therapeutic option with considerable translational benefit.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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A549 Cells
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Animals
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Antibodies, Blocking / pharmacology*
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Antibodies, Monoclonal / pharmacology*
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Cell Line, Tumor
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Disease Models, Animal
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HEK293 Cells
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Humans
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Imiquimod / toxicity
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Inflammation / pathology
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Interleukin-1 / immunology
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Interleukin-1 Receptor Accessory Protein / antagonists & inhibitors*
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Interleukin-1 Receptor Accessory Protein / immunology
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Interleukin-1beta / immunology
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Interleukin-33 / immunology
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Male
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Mice
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Mice, Inbred C57BL
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Ovalbumin / toxicity
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Peritonitis / drug therapy
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Peritonitis / immunology*
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Peritonitis / pathology
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Pneumonia / drug therapy
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Pneumonia / immunology*
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Pneumonia / pathology
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Psoriasis / drug therapy
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Psoriasis / immunology*
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Psoriasis / pathology
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Signal Transduction / immunology
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Uric Acid / toxicity
Substances
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Antibodies, Blocking
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Antibodies, Monoclonal
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IL1B protein, human
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IL1RAP protein, human
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IL33 protein, human
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IL36A protein, human
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Interleukin-1
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Interleukin-1 Receptor Accessory Protein
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Interleukin-1beta
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Interleukin-33
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Uric Acid
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Ovalbumin
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Imiquimod