IL-36 gamma [previously called IL-1F9, IL-1 epsilon (epsilon), and IL-1H1] is a member of the IL-1 family which includes IL-1 beta, IL-1 alpha, IL-1ra, IL-18, IL-36 Ra (IL-1F5), IL-36 alpha (IL-1F6), IL-36 beta (IL-1F8), IL-37 (IL-1F7) and IL-1F10. All family members show a 12 beta-strand, beta-trefoil configuration, and are believed to have arisen from a common ancestral gene. Mouse IL-36 gamma is an 18-22 kDa, 164 amino acid (aa) intracellular and secreted protein that contains no signal sequence, no prosegment and no potential N-linked glycosylation sites. Mouse IL-36 gamma (aa 13-164) shares 58%, 84%, 64% and 60% aa sequence identity with human, rat, equine and bovine IL-36 gamma, respectively, and 23-57% aa sequence identity with other family members. A 193 aa mouse isoform with a 29 aa N-terminal extension has been reported. Highest levels of IL-36 gamma are produced by Langerhans cells, keratinocytes, and stomach Chief cells and parietal cells; these cells contribute to first-line defense against pathogens in the skin, lungs and digestive tract. Its expression is induced by LPS treatment of monocytes, and by IL-alpha / beta, IL-17 or TNF-alpha treatment of keratinocytes and bronchial epithelia. Skin IL-36 gamma expression is increased in contact hypersensitivity and psoriasis. It is elevated in inflammatory disorders of the lung (such as asthma) and viral infections. Lung IL-36 gamma and other IL-36 proteins contribute to neutrophil influx. The receptor for IL-36 gamma is a combination of IL-1 Rrp2, mainly found in epithelia and keratinocytes, and the widely expressed IL-1 RAcP. IL-36 alpha, beta and gamma all activate NF-kappa B and MAPK pathways in an IL-1 Rrp2 dependent manner, and IL-36 gamma induces production of inflammatory cytokines and chemokines such as CXCL8/IL-8. Full-length recombinant IL-36 proteins appear less active than their endogenous counterparts, but trimming of the N-termini enhances their activity.

Mouse interleukin-36 beta [IL-36 beta ; previously IL-1F8, FIL-1 eta(eta) and IL-1H2] is a member of the IL-1 family of proteins that includes IL-1 beta, IL-1 alpha, IL-1ra, IL-18, IL-36Ra/IL-1F5, IL-36 alpha /IL-1F6, IL-37/IL-1F7, IL-36 gamma /IL-1F9 and IL-1F10. All family members show a 12 beta-stranded beta-trefoil configuration, share up to 50% amino acid (aa) sequence identity, and are believed to have arisen from a common ancestral gene. Although two alternatively spliced transcript variants for human IL-36 beta /IL-1F8 have been described, to date, only one mouse IL-36 beta /IL-1F8 isoform is known. Mouse IL-36 beta /IL-1F8 shares 61% and 74% aa identity with human IL-36 beta isoform 2 and rat IL-36 beta, respectively. IL-36 beta is agonistic, stimulating release of inflammatory mediators such as IL-6 and IL-8, and cytotoxic peptides such as beta-defensins 2 and 3 that aid in defense against microbial pathogens. The receptor for IL-36 proteins is IL-1 Rrp2, with IL-1 RAcP as a coreceptor. Antagonism of IL-36 proteins by IL-36Ra, which also binds IL-1 Rrp2, has been shown by some investigators. Skin keratinocytes express highest levels of IL-36 proteins and their receptors, followed by epithelia in the esophagus, trachea and bronchae. IL-36 beta expression is increased in psoriatic skin and may play a role in pathogenesis of psoriasis. IL-36 beta is also expressed in resting and activated monocytes and B cells, synovial fibroblasts, neurons and glia, and is detectable in plasma and body fluids. IL-36 beta, along with IL-36 alpha and IL-36 gamma, is up-regulated by IL-1 alpha and TNF- alpha in keratinocytes, and has been shown to activate NF- kappa B and MAPK signaling pathways in an IL-1 Rrp2-dependent manner. Full-length recombinant IL-36 proteins appear less active than their endogenous counterparts, but trimming of the N-termini enhances their activity.

IL36 alpha, previously called IL1F6 and FIL1 epsilon (family of IL1 member epsilon), is a member of the IL1 family which includes IL1 beta, IL1 alpha, IL1ra, IL18, and novel family members IL36 Ra (IL1F5), IL36 beta (IL1F8), IL36 gamma (IL1F9), IL37 (IL1F7) and IL1F10. All family members show a 12 beta strand, beta trefoil configuration, and are believed to have arisen from a common ancestral gene. It can be externalized nonspecifically in response to LPS and ATPinduced activation of the P2X7 receptor. Fulllength recombinant IL36 alpha is less active than endogenous IL36 alpha, but trimming of the Ntermini enhances its activity. Mouse IL36 alpha shares 83% aa sequence identity with rat IL36 alpha, 5460% with human, rabbit, equine and bovine IL36 alpha, and 2757% aa sequence identity with other novel IL1 family members. IL36 alpha is mainly found in skin and lymphoid tissues, but also in fetal brain, trachea, stomach and intestine. It is expressed by monocytes, B and T cells. The receptor for IL36 alpha is a combination of IL1 Rrp2 (also called IL1 RL2 or IL1 R6), mainly found in epithelia and keratinocytes, and the widely expressed IL1 RAcP. IL36 alpha, beta and gamma all activate NF kappa B and MAPK pathways in an IL1 Rrp2 dependent manner, and induce production of inflammatory cytokines and chemokines such as CXCL8/IL8. IL36 alpha and other family members are overexpressed in psoriatic skin lesions, and transgenic overexpression of IL36 alpha in skin keratinocytes produces epidermal hyperplasia. IL36 alpha is present in kidney tubule epithelia; it is highly overexpressed in tubulointerstitial lesions in mouse models of chronic glomerulonephritis, lupus nephritis and diabetic nephritis. IL36 alpha is induced by inflammation in adipose tissueresident alternately activated (M2) macrophages, and reduces adipocyte differentiation.