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.

Keratinocyte overexpression of IL-17C promotes psoriasiform skin inflammation.

IL-17C is a functionally distinct member of the IL-17 family that binds IL-17 receptor E/A to promote innate defense in epithelial cells and regulate Th17 cell differentiation. We demonstrate that IL-17C (not IL-17A) is the most abundant IL-17 isoform in lesional psoriasis skin (1058 versus 8 pg/ml; p < 0.006) and localizes to keratinocytes (KCs), endothelial cells (ECs), and leukocytes.

The anti-microbial peptide LL-37 modulates immune responses in the palatine tonsils where it is exclusively expressed by neutrophils and a subset of dendritic cells.

Antimicrobial peptides are essential elements of epithelial defense against invading micro-organisms. The palatine tonsils are positioned at the entry of the airway and the gut and as such are ideally situated to act as immune sentinels in the pharynx protecting against microbial invasion. Tonsils express a number of antimicrobial peptides including hCAP18/LL-37.

IL-1F5, -F6, -F8, and -F9: a novel IL-1 family signaling system that is active in psoriasis and promotes keratinocyte antimicrobial peptide expression.

IL-1F6, IL-1F8, and IL-1F9 and the IL-1R6(RP2) receptor antagonist IL-1F5 constitute a novel IL-1 signaling system that is poorly characterized in skin. To further characterize these cytokines in healthy and inflamed skin, we studied their expression in healthy control, uninvolved psoriasis, and psoriasis plaque skin using quantitative RT-PCR and immunohistochemistry. Expression of IL-1F5, -1F6, -1F8, and -1F9 were increased 2 to 3 orders of magnitude in psoriasis plaque versus uninvolved psoriasis skin, which was supported immunohistologically.

EGFR and IL-1 signaling synergistically promote keratinocyte antimicrobial defenses in a differentiation-dependent manner.

Ligands of the EGF family regulate autocrine keratinocyte proliferation, and IL-1 family cytokines orchestrate epithelial defense responses. Although members of both families are overexpressed in wound healing and psoriasis, their roles in regulating the innate immune functions of keratinocytes remain incompletely explored. Using sensitive assays, we found significant increases of heparin-binding EGF-like growth factor, transforming growth factor-α, and amphiregulin mRNA and protein in lesional psoriasis compared with uninvolved or control skin.

Assessment of the psoriatic transcriptome in a large sample: additional regulated genes and comparisons with in vitro models.

To further elucidate molecular alterations in psoriasis, we performed a gene expression study of 58 paired lesional and uninvolved psoriatic and 64 control skin samples. Comparison of involved psoriatic (PP) and normal (NN) skin identified 1,326 differentially regulated transcripts encoding 918 unique genes (549 up- and 369 downregulated), of which over 600 are to our knowledge previously unreported, including S100A7A, THRSP, and ELOVL3. Strongly upregulated genes included SERPINB4, PI3, DEFB4, and several S100-family members.