Search

The epidermis is the primary boundary between the body and the environment, and it serves as the first line of defense against microbial pathogens. Production of chemokines and cytokines is an important step in the initiation of innate immune responses to viral infections. Epidermal keratinocytes produce IFN-α, -β and macrophage inflammatory protein (MIP)-1α in response to double-stranded RNA (dsRNA) or viral infections. We showed that human keratinocytes produced cytokines [tumor necrosis factor (TNF)-α, IL-1β and IL-15] and chemokines [MIP-1β, RANTES and liver and activation-regulated chemokine (LARC)] in response to dsRNA, with activation of the nuclear factor κB (NF-κB), p38 mitogen-activated protein kinase (MAPK) and signal transducers and activators of transcription 1 (STAT1) pathways. To study the roles of these pathways in their production, we transfected keratinocytes with adenoviral vectors (Ax) carrying a dominant-negative form of inhibitor κB α (IκBα) (IκBαM), a dominant-negative mutant form of STAT1 (STAT1F) or suppressors of cytokine signaling 1 (SOCS1). Transfection with AxIκBαM or addition of a p38 inhibitor (SB203580) significantly decreased the dsRNA-mediated production of TNF-α, IL-1β and MIP-1α, but not of IFN-β, IL-15, MIP-1β, RANTES or LARC. Transfection with AxSTAT1F or AxSOCS1 inhibited the dsRNA-mediated production of TNF-α, IL-15, MIP-1α, MIP-1β, RANTES and LARC, but not IFN-β or IL-1β. In conclusion, the NF-κB, p38 MAPK and STAT1 pathways differentially regulate dsRNA-mediated innate immune responses in epidermal keratinocytes. [ABSTRACT FROM PUBLISHER]

The epidermis is constantly exposed to a variety of microbial pathogens and plays a vital role in resisting them. Soluble CXC chemokine ligand (CXCL) 16, which is one of the ELR− CXC chemokines, acts as a mediator of innate immunity by attracting CXC chemokine receptor (CXCR) 6-expressing cells, such as activated T cells and NKT cells. However, the production of CXCL16 by non-immune cells remains unclear. We found that cultured keratinocytes produced a significant amount of CXCL16 (2–3 ng per 106 cells per 24 h). Stimulation with tumor necrosis factor α, IL-1α, IFN-γ, peptidoglycan and polyinosinic-polycytidylic acid [poly(I:C)] enhanced CXCL16 production. The forms of CXCL16 in the culture supernatants had molecular weights of 14, 28 and 50 kDa. Immunohistochemical analysis revealed that the normal human epidermis expressed CXCL16. As several chemokines have anti-microbial activities, we studied the anti-microbial activity of CXCL16. The chemokine domain of CXCL16 at concentrations >5 μg ml−1 had significant anti-microbial activity against Staphylococcus aureus and Escherichia coli. Killing activity was retained at the physiological salt concentration in the presence of carbonate. In conclusion, CXCL16 is a novel mediator of the innate immune reactivities of epidermal keratinocytes. [ABSTRACT FROM AUTHOR]