Distinct expression of interleukin (IL)-36α, β and γ, their antagonist IL-36Ra and IL-38 in psoriasis, rheumatoid arthritis and Crohn's disease

Clin Exp Immunol. 2016 May;184(2):159-73. doi: 10.1111/cei.12761. Epub 2016 Feb 22.


Interleukin (IL)-36α, IL-36β and IL-36γ are expressed highly in skin and are involved in the pathogenesis of psoriasis, while the antagonists IL-36Ra or IL-38, another potential IL-36 inhibitor, limit uncontrolled inflammation. The expression and role of IL-36 cytokines in rheumatoid arthritis (RA) and Crohn's disease (CD) is currently debated. Here, we observed that during imiquimod-induced mouse skin inflammation and in human psoriasis, expression of IL-36α, γ and IL-36Ra, but not IL-36β and IL-38 mRNA, was induced and correlated with IL-1β and T helper type 17 (Th17) cytokines (IL-17A, IL-22, IL-23, CCL20). In mice with collagen-induced arthritis and in the synovium of patients with RA, IL-36α, β, γ, IL-36Ra and IL-38 were all elevated and correlated with IL-1β, CCL3, CCL4 and macrophage colony-stimulating factor (M-CSF), but not with Th17 cytokines. In the colon of mice with dextran sulphate sodium-induced colitis and in patients with CD, only IL-36α, γ and IL-38 were induced at relatively low levels and correlated with IL-1β and IL-17A. We suggest that only a minor subgroup of patients with RA (17-29%) or CD (25%) had an elevated IL-36 agonists/antagonists ratio, versus 93% of patients with psoriasis. By immunohistochemistry, IL-36 cytokines were produced by various cell types in skin, synovium and colonic mucosa such as keratinocytes, CD68⁺ macrophages, dendritic/Langerhans cells and CD79α⁺ plasma cells. In primary cultures of monocytes or inflammatory macrophages (M1), IL-36β and IL-36Ra were produced constitutively, but IL-36α, γ and IL-38 were produced after lipopolysaccharide stimulation. These distinct expression profiles may help to explain why only subgroups of RA and CD patients have a potentially elevated IL-36 agonists/antagonists ratio.

Keywords: Crohn's disease; IL-36; psoriasis; rheumatoid arthritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoquinolines
  • Animals
  • Arthritis, Experimental / immunology
  • Arthritis, Experimental / pathology
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / pathology*
  • Caco-2 Cells
  • Cell Line
  • Crohn Disease / immunology
  • Crohn Disease / pathology*
  • Dendritic Cells / metabolism
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Imiquimod
  • Inflammation / immunology
  • Inflammation / pathology
  • Interleukin-1 / biosynthesis*
  • Interleukin-1 / genetics
  • Interleukins / biosynthesis*
  • Interleukins / genetics
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / metabolism
  • Keratinocytes / metabolism
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Plasma Cells / metabolism
  • Psoriasis / immunology
  • Psoriasis / pathology*
  • RNA, Messenger / biosynthesis
  • Skin / metabolism
  • Synovial Membrane / cytology
  • Synovial Membrane / metabolism
  • Th17 Cells / immunology


  • Aminoquinolines
  • IL-38 protein, human
  • IL36A protein, human
  • IL36B protein, human
  • IL36G protein, human
  • IL36RN protein, human
  • Interleukin-1
  • Interleukins
  • RNA, Messenger
  • Imiquimod