Ouse dust mite protein Der p two (3-5) along with the metal nickel (six).authors for correspondence. Address correspondence and reprint requests to Dr. Tom Monie, Division of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, CB2 1QW, Uk, and Prof. Clare Bryant, Department of Veterinary Medicine, University of Cambridge, 80 Madingley Road, Cambridge, CB3 0ES, Uk. [email protected] (T.M.) and [email protected] (C.B.).Herre et al.PageDer p 2 is really a lipid binding protein that sensitizes ligand-induced signalling through TLR4 and TLR2 (3, four, 7). TLR4, in mixture with MD2 and CD14, recognizes bacterial lipopolysaccharides (LPS); and TLR2, in a heterodimer with either TLR1 or TLR6, recognizes di- and tri- NOP Receptor/ORL1 Agonist Storage & Stability acylated lipoproteins (8) and lipoteichoic acid (LTA). TLR5 recognises the bacterial protein flagellin (9, 10). Ligand recognition by TLRs then activates innate immune signalling pathways (11). Each MD2 and Der p two belong to a small family members of lipid binding proteins that have a sandwich or cup type fold (12). These proteins recognize lipid by intercalating their acyl chains in to the hydrophobic core with the sandwich. Therefore, one prospective mechanism by which Der p two enhances TLR4 signalling should be to mimic MD2 by binding to TLR4. The Der p 2/TLR4 protein complex may well then signal like MD2/TLR4 to activate innate immune signalling (four). In mouse models of allergic asthma the effects of Der p two are markedly decreased in TLR4 knockout mice and may be prevented in wild sort mice by administration of a TLR4 antagonist (7). Property dust mite extracts carrying flagellin can induce TLR5-dependent allergic responses in mice, while the molecular mechanism by which this occurs is unclear (five). Nickel sensitization in humans outcomes from direct, lipid independent activation of TLR4 by Ni2+. Receptor activation is dependent around the presence of two histidine residues, H456 and H458, which co-ordinate the Ni2+ atom (or other metal ions including Co2+), promoting TLR4 dimerisation and subsequent receptor activation. Murine TLR4 lacks these histidines and consequently is not activated by nickel (six, 13). An additional clinically important allergen is definitely the cat dander protein Fel d 1, which is the commonest cause of severe allergic responses to cats in man (14). In contrast to Der p 2 this allergen has an totally Topo II Inhibitor Compound alpha-helical structure (15) and is hence unlikely to act as a mimetic of MD2. Fel d 1 can bind to the mannose receptor, but immune signalling just isn’t initiated following engagement of this receptor (16). Hence the mechanism by which this protein initiates an allergic response remains unclear. In this paper we propose a mechanism by which Fel d 1 is recognized by the host to activate immune signalling. Fel d 1 enhances LPS and LTA, but not flagellin-induced TLR signalling. In contrast to Der p two, the mechanism for Fel d 1 enhancement of LPS-induced TLR4/ MD2 activation will not involve the protein binding for the TLRs, but does need the presence of CD14. The dog dander protein Can f 6 (17), a structurally distinct allergen from Fel d 1 and a member of your lipocalin family of allergens, also enhances LPS-induced activation of TLR4 signalling although, in contrast to Fel d 1, this protein has some MD2 independent effects. We propose, therefore, that animal allergen proteins type a novel class of immune modulator proteins (IMPs) that improve TLR signalling and therefore play a essential part in initiating allergic responses. The mechanism for TLR enhancement of sign.
