Increased serum human β-defensin-2 levels in atopic dermatitis: Relationship to IL-22 and oncostatin M

Atopic dermatitis (AD) is associated with dysregulated expression of human β-defensins (hBDs) and infiltration of T cells producing cytokines which regulate hBD expression. We examined serum levels of hBDs and cytokines in AD patients, the effects of cytokines on hBD production in human keratinocytes, and those of hBDs on cytokine production in human peripheral blood-derived T cells. Levels of serum hBD-2, IL-22, and oncostatin M, but not hBD-3, were higher in AD patients than in normal donors. Serum hBD-2 levels of AD patients correlated with AD scoring and IL-22 levels. IL-22 and oncostatin M enhanced hBD-2 production and signal transducer and activator of transcription 3 (STAT3) activities strongly and hBD-3 production moderately in human keratinocytes. STAT3 inhibitor suppressed IL-22 and oncostatin M-induced production of hBD-2 and hBD-3. hBD-2 strongly and hBD-3 moderately enhanced IL-22 and oncostatin M production, whereas hBD-3 strongly and hBD-2 moderately enhanced IL-31, IL-13, and IL-4 production in CD3/28-stimulated T cells. hBD-2 induced phosphorylation of c-Jun N-terminal kinase, extracellular signal-regulated kinase, and Akt, while hBD-3 induced phosphorylation of inhibitory κB kinase, p38 mitogen-activated protein kinase, and Akt in CD3/28-stimulated T cells. Inhibitors of these signals attenuated hBD-2- or hBD-3-induced production of cytokines. These results suggest that serum hBD-2 may be a biomarker of skin inflammation. IL-22 and oncostatin M may enhance hBD-2 production via STAT3 in keratinocytes, while hBD-2 may enhance IL-22 and oncostatin M production in T cells. hBD-3 may enhance TH2 responses.