IL-1ß-Induced Protection of Keratinocytes against Staphylococcus aureus-Secreted Proteases Is Mediated by Human ß-Defensin 2.

Atopic dermatitis (AD) is a common chronic inflammatory skin disease that results in significant morbidity. A hallmark of AD is disruption of the critical barrier function of upper epidermal layers, causatively linked to environmental stimuli, genetics, and infection, and a critical current target for the development of new therapeutic and prophylactic interventions. Staphylococcus aureus is an AD-associated pathogen producing virulence factors that induce skin barrier disruption in vivo and contribute to AD pathogenesis. We show, using immortalized and primary keratinocytes, that S. aureus protease SspA/V8 is the dominant secreted factor (in laboratory and AD clinical strains of S. aureus) inducing barrier integrity impairment and tight junction damage. V8-induced integrity damage was inhibited by an IL-1ß-mediated mechanism, independent of effects on claudin-1. Induction of keratinocyte expression of the antimicrobial/host defense peptide human ß-defensin 2 (hBD2) was found to be the mechanism underpinning this protective effect. Endogenous hBD2 expression was required and sufficient for protection against V8 protease-mediated integrity damage, and exogenous application of hBD2 was protective. This modulatory property of hBD2, unrelated to antibacterial effects, gives new significance to the defective induction of hBD2 in the barrier-defective skin lesions of AD and indicates therapeutic potential.

Comparing the lifetime risks of TNF-alpha inhibitor use to common benchmarks of risk.

OBJECTIVE: The study aims to illustrate the range of lifetime risks of lymphoma, tuberculosis (TB), and demyelinating diseases with TNF-α inhibitors in psoriasis patients. METHODS: Previously published data and online resources were used to determine the risk of the TB, demyelinating disease, and lymphoma with and without TNF-α inhibitor treatment. Lifetime risks for heart disease and stroke were collected using a Medline search. All cancer, trauma, and environmental statistics were obtained from the data published by National Cancer Institute, National Safety Council, and the National Oceanic and Atmospheric Administration, respectively. RESULTS: The lifetime risks of TNF-α-inhibitor-linked conditions and comparators are as follows: TNF-α inhibitor-linked conditions: lymphoma with: without TNF-α inhibitors (0.5-4.8%:2.3%), TB with:without TNF-α inhibitors (0-17.1%:0.3%), and demyelinating disease with:without TNF-α inhibitors (0.1-1.7%:0.15%). Comparators: cancer (40.4%), heart disease (36.2%), stroke (18.4%), accidental death (3.0%), motor vehicle death (1.2%), and lightning strike (0.033%). LIMITATIONS: Much of the data on lifetime risks of disease with TNF-α inhibitor were for patients with rheumatoid arthritis and not psoriasis. CONCLUSIONS: The risks of lymphoma, demyelinating diseases, and tuberculosis with TNF-α inhibitors are lower than risks patients face on a regular basis. Screening reduces the risk of tuberculosis in patients receiving TNF-α inhibitors.