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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. Multiple cytokines in the proinflammatory IL-1 family share the co-receptor IL-1R3. Dinarello and colleagues show that a fully humanized antibody to IL-1R3 can effectively control inflammation and disease mediated not only by IL-1 but also by IL-33 and IL-36.

For more than a decade, it has been known that NF-kappa B is constitutively activated in a majority of acute myeloid leukemia (AML) patients which contributes to the resistance to apoptosis. Inhibition of NF-kappa B has been shown to induce apoptosis in AML cells, but the clinical effectiveness of NF-kappa B inhibitors has been inadequate. In recent years, possible causes underlying this continuous NF-kappa B activity have been elucidated. It has been shown that chromosomal translocations or mutations leading to development of leukemia drive the increase in NF-kappa B activity. Furthermore, autocrine/paracrine cytokine signaling and increased expression of NF-kappa B signaling components play an important role in the continuous NF-kappa B activation. Moreover, high proteasome activity, which positively regulates NF-kappa B activity, is often observed in AML patients. In the present study, we described these underlying molecular mechanisms leading to constitutive NF-kappa B activity and discussed the novel treatment strategies based on the inhibition of NF-kappa B activation. (C)2015 Elsevier Ireland Ltd. All rights reserved.

For more than a decade, it has been known that NF-kappa B is constitutively activated in a majority of acute myeloid leukemia (AML) patients which contributes to the resistance to apoptosis. Inhibition of NF-kappa B has been shown to induce apoptosis in AML cells, but the clinical effectiveness of NF-kappa B inhibitors has been inadequate. In recent years, possible causes underlying this continuous NF-kappa B activity have been elucidated. It has been shown that chromosomal translocations or mutations leading to development of leukemia drive the increase in NF-kappa B activity. Furthermore, autocrine/paracrine cytokine signaling and increased expression of NF-kappa B signaling components play an important role in the continuous NF-kappa B activation. Moreover, high proteasome activity, which positively regulates NF-kappa B activity, is often observed in AML patients. In the present study, we described these underlying molecular mechanisms leading to constitutive NF-kappa B activity and discussed the novel treatment strategies based on the inhibition of NF-kappa B activation. (C)2015 Elsevier Ireland Ltd. All rights reserved.