The Role of Interleukin-1 in Inflammatory and Malignant Human Skin Diseases and the Rationale for Targeting Interleukin-1 Alpha

Abstract

Inflammation plays a major role in the induction and progression of several skin diseases. Overexpression of the major epidermal proinflammatory cytokines interleukin (IL) 1 alpha (IL-1α) and 1 beta (IL-1β) is positively correlated with symptom exacerbation and disease progression in psoriasis, atopic dermatitis, neutrophilic dermatoses, skin phototoxicity, and skin cancer. IL-1β and the interleukin-1 receptor I (IL-1RI) have been used as a therapeutic target for some autoinflammatory skin diseases; yet, their system-wide effects limit their clinical usage. Based on the local effects of extracellular IL-1α and its precursor, pro-IL-1α, we hypothesize that this isoform is a promising drug target for the treatment and prevention of many skin diseases. This review provides an overview on IL-1α and IL-β functions, and their contribution to inflammatory and malignant skin diseases. We also discuss the current treatment regimens, and ongoing clinical trials, demonstrating the potential of targeting IL-1α, and not IL-1β, as a more effective strategy to prevent or treat the onset and progression of various skin diseases.

Structural basis for IL-1α recognition by a modified DNA aptamer that specifically inhibits IL-1α signaling

“…The scope of human diseases for which IL-1α involvement has been implicated is extensive and diverse and includes Type 2 diabetes 18 , cancer 12 , 13 , 60 , cancer cachexia 61 , leukemia 62 , psoriasis 63 , vascular disease 15 , 17 , and scarring acne vulgaris 18 . Therapeutic intervention of IL-1RI signaling via antagonism of IL-1α is therefore of great interest.…”

The Role of Interleukin-1 in the Pathogenesis of Cancer and its Potential as a Therapeutic Target in Clinical Practice

“…Ovarian cancer Overexpression of IL-1b/IL1-I1 represses p53 tumor suppressor [75] Pancreatic cancer Overexpression and secretion of IL-1b by CD133? tumor-initiating cancer stem cells and TAMs [57,58] Prostate cancer Activation of TR4/Oct4/IL-1Ra axis confers chemotherapy resistance [78] Both IL-1 agonists are known to play important roles in many benign and malignant skin diseases, as review by Bou-Dargham et al They suggest focusing on IL-1a as the main target of IL-1 immunotherapy in skin cancer because of the unique expression of IL-1a and its bioactive pre-IL-1a in different skin cell types [71]. Elevated levels of IL-1b were found in hematologic cancers, such as multiple myeloma (MM) and some types of lymphoma compared with healthy controls [72,73].…”

TWEAK/Fn14 Activation Participates in Skin Inflammation

“…Recently, it was reported that TWEAK/Fn14 interaction increases the expression and/or secretion of various molecules involved in local inflammatory responses [ 38 – 40 ]. Moreover, TWEAK promotes the proinflammatory activities of other cytokines such as TNF- α , interleukin- (IL-) 1, IL-6, and interferon- γ [ 28 , 41 ], which also participate in the pathogenesis of inflammatory skin diseases [ 28 , 42 , 43 ]. Therefore, these findings suggest a pivotal role of TWEAK/Fn14 pathway in the mechanism of cutaneous inflammation.…”