Staphylococcus aureus membrane and diacylated lipopeptide induce thymic stromal lymphopoietin in keratinocytes through the Toll-like receptor 2-Toll-like receptor 6 pathway.
BACKGROUND
Staphylococcus aureus heavily colonizes the lesions of patients with atopic dermatitis (AD) and is known to trigger a worsening of AD. However, the exact mechanism by which S. aureus promotes AD is unknown. Thymic stromal lymphopoietin (TSLP), which is highly expressed by keratinocytes in skin lesions of patients with AD and bronchial epithelial cells in asthmatic patients, represents a critical factor linking responses at interfaces between the body and the environment to allergic type 2 immune responses.


OBJECTIVE
We sought to examine the ability of synthetic lipopeptides and S. aureus to induce TSLP expression in human keratinocytes and identify the pathway of induction.


METHODS
We stimulated primary human keratinocytes with lipopeptides and S. aureus-derived materials. The release and gene expression of TSLP were measured by means of ELISA and quantitative PCR, respectively.


RESULTS
Diacylated lipopeptide upregulated the expression of TSLP and other proinflammatory molecules. Heat-killed S. aureus and the subcellular fractions of S. aureus induced TSLP's release, with the membranous fraction having the greatest activity. Small interfering RNA-mediated knockdown of either Toll-like receptor (TLR) 2 or TLR6 inhibited the diacylated lipopeptide- and S. aureus membrane-induced TSLP gene expression. S. aureus membrane- and diacylated lipopeptide-induced release of TSLP was enhanced by T(H)2/TNF-α cytokines and partially suppressed by IFN-γ and TGF-β.


CONCLUSIONS
The results suggest that ligands for the TLR2-TLR6 heterodimer in S. aureus membranes, including diacylated lipoproteins, could promote T(H)2-type inflammation through TSLP production in keratinocytes, providing an overall picture of the vicious cycles between colonization by S. aureus and AD in the T(H)2-skewed sensitization process, exacerbation of the disease, or both.
Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
Anh Tuan
AT
Vu
Tadashi
T
Baba
Xue
X
Chen
Tuan Anh
TA
Le
Hirokazu
H
Kinoshita
Yang
Y
Xie
Seiji
S
Kamijo
Keiichi
K
Hiramatsu
Shigaku
S
Ikeda
Hideoki
H
Ogawa
Ko
K
Okumura
Toshiro
T
Takai
D000942:Antigens, Bacterial / Q000276:immunology*; D002462:Cell Membrane / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology*; D003876:Dermatitis, Atopic / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D006801:Humans; D015603:Keratinocytes / Q000276:immunology* / Q000378:metabolism; D055666:Lipopeptides / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D013203:Staphylococcal Infections / Q000276:immunology; D013211:Staphylococcus aureus / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology*; D051216:Toll-Like Receptor 6 / Q000276:immunology*; D000094632:Thymic Stromal Lymphopoietin
D000942:Antigens, Bacterial; D016207:Cytokines; D055666:Lipopeptides; C495342:TLR2 protein, human; C495368:TLR6 protein, human; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6; D000094632:Thymic Stromal Lymphopoietin