Human IL-36 alpha, previously called IL-1F6 and FIL1 epsilon (family of IL-1 member epsilon), is a member of the IL-1 family which includes IL-1 beta, IL-1 alpha, IL-1ra, IL-18, and novel family members IL-36 Ra (IL-1F5), IL-36 beta (IL-1F8), IL-36 gamma (IL-1F9), IL-37 (IL-1F7) and IL- 38 (IL- 1F10) . All family members show a 12 beta -strand, beta -trefoil configuration, and are believed to have arisen from a common ancestral gene. IL-36 alpha is an 18- 22 kDa, 158 amino acid (aa) intracellular and secreted protein that contains no signal sequence, no prosegment and no potential from N-linked glycosylation sites. It can be released in response to LPS and the cell ATP-induced activation of the P2X7 receptor. A 120 aa isoform missing aa 1- 38 has been reported. Human IL- 36 alpha (aa 6 - 158) shares 57- 68% aa sequence identity with mouse, rabbit, equine and bovine IL- 36 alpha and 27- 57% aa sequence identity with other novel IL- 1 family members. IL- 36 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 IL- 36 alpha is a combination of IL- 1 Rrp2 (also called IL1RL2 or IL- 1 R6), 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 induce production of inflammatory cytokines and chemokines such as CXCL8/IL-8. IL-36 alpha and other family members are overexpressed in psoriatic skin lesions, and transgenic overexpression of IL- 36 alpha in skin keratinocytes produces epidermal hyperplasia. IL-36 alpha is present in kidney tubule epithelia, and it is highly expressed in intubulointerstitial lesions in mouse models of chronic glomerulonephritis, lupus nephritis and diabetic nephritis.
