Abstract
Allergies to nickel (Ni(2+)) are the most frequent cause of contact hypersensitivity (CHS) in industrialized countries. The efficient development of CHS requires both a T lymphocyte-specific signal and a proinflammatory signal. Here we show that Ni(2+) triggered an inflammatory response by directly activating human Toll-like receptor 4 (TLR4). Ni(2+)-induced TLR4 activation was species-specific, as mouse TLR4 could not generate this response. Studies with mutant TLR4 proteins revealed that the non-conserved histidines 456 and 458 of human TLR4 are required for activation by Ni(2+) but not by the natural ligand lipopolysaccharide. Accordingly, transgenic expression of human TLR4 in TLR4-deficient mice allowed efficient sensitization to Ni(2+) and elicitation of CHS. Our data implicate site-specific human TLR4 inhibition as a potential strategy for therapeutic intervention in CHS that would not affect vital immune responses.
Original language | English |
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Pages (from-to) | 814-819 |
Number of pages | 0 |
Journal | Nat Immunol |
Volume | 11 |
Issue number | 9 |
DOIs | |
Publication status | Published - Sept 2010 |
Keywords
- Amino Acid Sequence
- Animals
- Dermatitis
- Contact
- Disease Models
- Animal
- Humans
- Mice
- Transgenic
- Models
- Molecular
- Molecular Sequence Data
- Nickel
- Recombinant Proteins
- Signal Transduction
- Toll-Like Receptor 4