(a) Members of the Interleukin-1 (IL-1) family of cytokines and their receptors inside a keratinocyte. To exert its pro-inflammatory effect, Interleukin-1 alpha (IL-1α) and Interleukin-1 beta (IL-1β) bind to Interleukin-1 receptor type 1 (IL-1R1) and recruits Interleukin-1 receptor accessory protein (IL-1R3). Interleukin-1 receptor antagonist (Il-1Ra) is a natural anti-inflammatory protein that suppresses the pro-inflammatory effect of Interleukin-1. Interleukin-33 (IL-33) binds to receptor ST2 and further recruits Interleukin-1 receptor accessory protein (IL-1R3) to exert its pro-inflammatory effect. Interleukin-36 alpha (IL-36α), Interleukin-36 beta (IL-36β), and Interleukin-36 gamma (IL-36γ) bind to Interleukin-36 receptor (IL-36R) and recruit Interleukin-1 receptor accessory protein (IL-1R3) to induce inflammation, while Interleukin-36 receptor antagonist (IL-36Ra) and Interleukin-18 (IL-18) suppress this binding. IL-18 cytokine binds to interleukin-18 receptor alpha (1L18Rα) and recruits interleukine-18 receptor beta (1L18Rβ) to stimulate the production of IFN-γ, inducing a Th2 and Th1 response. Interleukin-18 binding protein (IL18-BP) regulates its pro-inflammatory activity by creating a negative feedback mechanism by sequestering the cytokine Interleukin 37 (IL-37) to bind to interleukin-18 receptor alpha (1L18Rα) and restrict the interleukin-18 receptor (1L-18R)-dependent inflammation and inhibiting its pro-inflammatory cytokine production. The binding of these cytokines to these specific ligands results in activation of NFKB or MAPK signaling pro-inflammatory gene expression through MyD88, IRAF, and/or TRAF6 signaling mechanisms. MyD88, Myeloid differentiation primary response 88; IRAF, interferon regulatory factor; TRAF6, TNF-receptor-associated factor 6; NFKB, Nuclear factor kappa-light-chain-enhancer of activated B cells; MAPK, mitogen-activated protein kinase 11. This figure was created with Biorender at www.biorender.com. (b) Mechanism of action of different drugs acting on the members of the Interleukin-1 (IL-1) family of cytokines and their receptors inside a keratinocyte. Bermekimab, a fully human monoclonal antibody that targets IL-1α. Canakinumab, a fully human monoclonal antibody against IL-1β. Gevokizumab, a neutralizing humanized monoclonal antibody specific to IL-1β. Etokimab is a humanized anti-IL-33 monoclonal antibody. Itepekimab (REGN3500) is an anti-IL33 antibody. Tozorakimab (MEDI3506) inhibits IL33 signaling via IL33R/ST2 pathway. Astegolimab, a fully human IgG2 monoclonal antibody that binds to ST2. Spesolimab, an antibody against IL36R. Tadekinig alfa is human recombinant IL-18-binding protein that neutralizes IL-18. MyD88, Myeloid differentiation primary response 88; IRAF, interferon regulatory factor; TRAF6, TNF-receptor-associated factor 6; NFKB, Nuclear factor kappa-light-chain-enhancer of activated B cells; MAPK, mitogen-activated protein kinase 11. This figure was created with Biorender at www.biorender.com.
