IL-36 promotes myeloid cell infiltration, activation, and inflammatory activity in skin.
The IL-1 family members IL-36α (IL-1F6), IL-36β (IL-1F8), and IL-36γ (IL-1F9) and the receptor antagonist IL-36Ra (IL-1F5) constitute a novel signaling system that is poorly understood. We now show that these cytokines have profound effects on the skin immune system. Treatment of human keratinocytes with IL-36 cytokines significantly increased the expression of CXCL1, CXCL8, CCL3, CCL5, and CCL20, potent chemotactic agents for activated leukocytes, and IL-36α injected intradermally resulted in chemokine expression, leukocyte infiltration, and acanthosis of mouse skin. Blood monocytes, myeloid dendritic cells (mDC), and monocyte-derived DC (MO-DC) expressed IL-36R and responded to IL-36. In contrast, no direct effects of IL-36 on resting or activated human CD4(+) or CD8(+) T cells, or blood neutrophils, could be demonstrated. Monocytes expressed IL-1A, IL-1B, and IL-6 mRNA and IL-1β and IL-6 protein, and mDC upregulated surface expression of CD83, CD86, and HLA-DR and secretion of IL-1β and IL-6 after treatment with IL-36. Furthermore, IL-36α-treated MO-DC enhanced allogeneic CD4(+) T cell proliferation, demonstrating that IL-36 can stimulate the maturation and function of DC and drive T cell proliferation. These data indicate that IL-36 cytokines actively propagate skin inflammation via the activation of keratinocytes, APC, and, indirectly, T cells.
Department of Dermatology, University of Michigan, Ann Arbor, MI 48109; and.
Alexander M
AM
Foster
Department of Dermatology, University of Michigan, Ann Arbor, MI 48109; and.
Jaymie
J
Baliwag
Department of Dermatology, University of Michigan, Ann Arbor, MI 48109; and.
Cynthia S
CS
Chen
Department of Dermatology, University of Michigan, Ann Arbor, MI 48109; and.
Andrew M
AM
Guzman
Department of Dermatology, University of Michigan, Ann Arbor, MI 48109; and.
Stefan W
SW
Stoll
Department of Dermatology, University of Michigan, Ann Arbor, MI 48109; and.
Johann E
JE
Gudjonsson
Department of Dermatology, Case Western Reserve University, Cleveland, OH 44106.
Nicole L
NL
Ward
Department of Dermatology, University of Michigan, Ann Arbor, MI 48109; and andjoh@med.umich.edu.
Andrew
A
Johnston
D064591:Allografts; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement / Q000276:immunology*; D049109:Cell Proliferation; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D003872:Dermatitis / Q000276:immunology* / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D007375:Interleukin-1 / Q000276:immunology* / Q000494:pharmacology; D015603:Keratinocytes / Q000276:immunology* / Q000473:pathology; D051379:Mice; D009000:Monocytes / Q000276:immunology* / Q000473:pathology; D012867:Skin / Q000276:immunology* / Q000473:pathology; D016038:Skin Transplantation
D016207:Cytokines; D007375:Interleukin-1