Interleukin 36, or IL-36, is a group of cytokines in the IL-1 family with pro-inflammatory effects. The role of IL-36 in inflammatory diseases is under investigation. [1]
There are four members of the IL-36 family which bind to the IL-36 receptor ( IL1RL2/IL-1Rrp2/IL-36 receptor dimer) with varying affinities. [2] IL36A, IL36B, and IL36G are IL-36 receptor agonists. IL36RA is an IL-36 receptor antagonist, inhibiting IL-36R signaling. The agonists are known to activate NF-κB, mitogen-activated protein kinases, Erk1/2 and JNK through IL-36R/IL-1RAcP, which targets the IL-8 promotor and results in IL-6 secretion and induces various proinflammatory mediators. [3] [4] Binding of the IL-36R agonists to IL-1Rrp2 recruits IL-1RAcP, activating the signaling pathway. IL-36Ra binds to IL-36R, preventing the recruitment of IL-1RAcP. [1]
IL-36 has been found to activate T cell proliferation and release of IL-2. [5] Before the functions of the IL-36 cytokines were determined, they were named as derivatives of IL-1F; they were renamed to their current designations in 2010. [6]
Due to their predominant expression in epithelial tissues, IL-36 cytokines are believed to play a significant role in the pathogenesis of skin diseases, especially that of psoriasis. [6] IL-36 has also been linked to psoriatic arthritis, systemic lupus erythematosus, inflammatory bowel disease, ulcerative colitis, Crohn's disease, and Sjögren's syndrome. [1]
IL-36 must be cleaved at the N-terminus to become active, probable enzymes mediating the activation could be neutrophil granule-derived proteases, elastase, and cathepsin G, although they may activate the cytokines differentially. [7]
IL-36 is expressed by many cells types, most predominantly keratinocytes, respiratory epithelium, various nervous tissue, and monocytes. [6] [1]
The genes encoding for the IL-36 cytokines are found on chromosome 2q14.1. [8] [9] [10] All three are located in a cluster with other members of IL-1 family and the gene order from centromere to telomere is IL-1A-IL-1B-IL-37-IL-36G-IL-36A-IL-36B-IL-36RN-IL1F10-IL-1RN, and only IL-1A, IL-1B and IL-36B. [11] All of them probably arose from a common ancestral gene, which is most likely a primordial IL-1 receptor antagonist gene. [12]
All three genes are mainly expressed in keratinocytes, bronchial epithelium, brain tissue, and monocytes/macrophages. [6] In the epidermis IL-36 cytokine expression is limited to granular layer keratinocytes with little to no expression in basal layer keratinocytes. [13]
IL-36Ra is constitutively expressed in keratinocytes, whereas IL-36γ expression in keratinocytes is rapidly induced after stimulation with TNF or PMA (Phorbol 12-myristate 13-acetate). [14]
IL-36-alpha functions primarily in skin and demonstrates increased expression in psoriasis. In addition, decreased expression of this gene has been linked to a poor prognosis in both hepatocellular carcinoma and colorectal cancer patients. [6]
IL-36 cytokines may play a regulatory role in the pathogenesis of inflammatory disorders such as folliculitis and eosinophilic pustular folliculitis. In addition, in acute generalized exanthematous pustulosis, IL-36 (mainly IL-36 gamma) was overexpressed in skin lesions. [15]
Studies revealed that T cells were sufficient to cause skin inflammation after Staphylococcus aureus exposure on mice, mediating the skin inflammation via IL-36-controlled, IL-17-dependent T cell responses. [16]
IL-36 is significantly involved in the pathogenesis of psoriasis leading to it being targeted therapeutically. Human psoriatic skin plaques displayed elevated IL-36beta. In addition, It was found that serum IL-36 levels are higher in patients with psoriasis vulgaris and its levels positively correlate with disease activity, suggesting that serum IL-36 levels might serve as useful biomarkers in patients with psoriasis. [17]
Interleukin 36, or IL-36, is a group of cytokines in the IL-1 family with pro-inflammatory effects. The role of IL-36 in inflammatory diseases is under investigation. [1]
There are four members of the IL-36 family which bind to the IL-36 receptor ( IL1RL2/IL-1Rrp2/IL-36 receptor dimer) with varying affinities. [2] IL36A, IL36B, and IL36G are IL-36 receptor agonists. IL36RA is an IL-36 receptor antagonist, inhibiting IL-36R signaling. The agonists are known to activate NF-κB, mitogen-activated protein kinases, Erk1/2 and JNK through IL-36R/IL-1RAcP, which targets the IL-8 promotor and results in IL-6 secretion and induces various proinflammatory mediators. [3] [4] Binding of the IL-36R agonists to IL-1Rrp2 recruits IL-1RAcP, activating the signaling pathway. IL-36Ra binds to IL-36R, preventing the recruitment of IL-1RAcP. [1]
IL-36 has been found to activate T cell proliferation and release of IL-2. [5] Before the functions of the IL-36 cytokines were determined, they were named as derivatives of IL-1F; they were renamed to their current designations in 2010. [6]
Due to their predominant expression in epithelial tissues, IL-36 cytokines are believed to play a significant role in the pathogenesis of skin diseases, especially that of psoriasis. [6] IL-36 has also been linked to psoriatic arthritis, systemic lupus erythematosus, inflammatory bowel disease, ulcerative colitis, Crohn's disease, and Sjögren's syndrome. [1]
IL-36 must be cleaved at the N-terminus to become active, probable enzymes mediating the activation could be neutrophil granule-derived proteases, elastase, and cathepsin G, although they may activate the cytokines differentially. [7]
IL-36 is expressed by many cells types, most predominantly keratinocytes, respiratory epithelium, various nervous tissue, and monocytes. [6] [1]
The genes encoding for the IL-36 cytokines are found on chromosome 2q14.1. [8] [9] [10] All three are located in a cluster with other members of IL-1 family and the gene order from centromere to telomere is IL-1A-IL-1B-IL-37-IL-36G-IL-36A-IL-36B-IL-36RN-IL1F10-IL-1RN, and only IL-1A, IL-1B and IL-36B. [11] All of them probably arose from a common ancestral gene, which is most likely a primordial IL-1 receptor antagonist gene. [12]
All three genes are mainly expressed in keratinocytes, bronchial epithelium, brain tissue, and monocytes/macrophages. [6] In the epidermis IL-36 cytokine expression is limited to granular layer keratinocytes with little to no expression in basal layer keratinocytes. [13]
IL-36Ra is constitutively expressed in keratinocytes, whereas IL-36γ expression in keratinocytes is rapidly induced after stimulation with TNF or PMA (Phorbol 12-myristate 13-acetate). [14]
IL-36-alpha functions primarily in skin and demonstrates increased expression in psoriasis. In addition, decreased expression of this gene has been linked to a poor prognosis in both hepatocellular carcinoma and colorectal cancer patients. [6]
IL-36 cytokines may play a regulatory role in the pathogenesis of inflammatory disorders such as folliculitis and eosinophilic pustular folliculitis. In addition, in acute generalized exanthematous pustulosis, IL-36 (mainly IL-36 gamma) was overexpressed in skin lesions. [15]
Studies revealed that T cells were sufficient to cause skin inflammation after Staphylococcus aureus exposure on mice, mediating the skin inflammation via IL-36-controlled, IL-17-dependent T cell responses. [16]
IL-36 is significantly involved in the pathogenesis of psoriasis leading to it being targeted therapeutically. Human psoriatic skin plaques displayed elevated IL-36beta. In addition, It was found that serum IL-36 levels are higher in patients with psoriasis vulgaris and its levels positively correlate with disease activity, suggesting that serum IL-36 levels might serve as useful biomarkers in patients with psoriasis. [17]