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Serum amyloid A (SAA) is a highly conserved acute-phase protein and extrahepatic produced SAA1/2 contributes to cutaneous inflammation. Prolonged systemic or topical treatment with glucocorticoids can provoke skin diseases such as steroid-induced acne. Glucocorticoids increase Toll-like receptor 2 (TLR2) expression, however, an inflammatory mediator linked to this side effect remains elusive. We report that TLR2 agonists in combination with dexamethasone substantially increase SAA expression and production in human keratinocytes and epithelial cells. Dexamethasone-mediated SAA1 induction depends on the glucocorticoid receptor (GR). In response to Propionibacterium acnes, TLR2-activated signal transducer and activator of transcription 3 (STAT3) and nuclear factor κB (NF-κB) signaling pathways are critically involved in dexamethasone-induced SAA1 production. The formation of transcription factor complexes between GR or p300 and phospho-STAT3 was confirmed by co-immunoprecipitation in dexamethasone- and P. acnes-stimulated keratinocytes. Furthermore, dexamethasone and P. acnes-increased TLR2 and mitogen-activated protein kinase phosphatase-1 (MKP-1) contribute to induction of SAA1 and 2. Likewise, tumor necrosis factor (TNF) induces SAA1 in combination with dexamethasone. GR, transcription factors STAT3 and NF-κB, but not MKP-1, mediate TNF- and dexamethasone-induced SAA1. Conclusively, we provide evidence that glucocorticoids promote SAA1 production under infectious and sterile inflammatory conditions which may provide significant insights to the pathogenesis of steroid-induced acne.