Short-form human MD-2 as a negative regulator of toll-like receptor 4 signaling
The present invention is based on a novel, alternatively spliced human isoform of MD-2 (MD-2s). In addition, the present invention relates to modified MD-2 proteins, wherein one or more tyrosine residues have been mutated to phenylalanine. In various embodiments, the invention relates to methods and kits for preventing, reducing the likelihood of developing and/or treating various conditions using MD-2s. The invention also describes methods of determining the risk of a subject to various conditions.
1. A method of inhibiting lipopolysaccharide (“LPS”) activated toll-like receptor 4 signaling (“TLR4”), inhibiting LPS signaling, or inhibiting LPS induced inflammation in a subject in need thereof, comprising:
providing a purified polypeptide comprising an amino acid sequence that is at least 80% identical to SEQ ID NO: 1 or SEQ ID NO:2; and
administering the polypeptide to the subject to inhibit LPS activated TLR4 signaling, inhibit LPS signaling, or inhibit LPS induced inflammation.
2. The method of claim 1 , wherein the polypeptide comprises the amino acid sequence of SEQ ID NO:1.
3. The method of claim 2 , wherein the polypeptide is glycosylated.
4. The method of claim 1 , wherein the polypeptide comprises the amino acid sequence of SEQ ID NO:1 and 1-20 conservative amino acid substitutions.
5. The method of claim 1 , wherein the polypeptide comprises the amino acid sequence of SEQ ID NO:1 and 1-20 amino acid insertions, deletions and/or substitutions.
6. The method of claim 1 , wherein the polypeptide comprises the amino acid sequence of SEQ ID NO:2.
7. The method of claim 6 , wherein the polypeptide is glycosylated.
8. The method of claim 1 , wherein the polypeptide comprises the amino acid sequence of SEQ ID NO:2 and 1-20 conservative amino acid substitutions.
9. The method of claim 1 , wherein the polypeptide comprises the amino acid sequence of SEQ ID NO:2 and 1-20 amino acid insertions, deletions and/or substitutions.
10. The method of claim 1 , wherein LPS activated TLR4 signaling is inhibited.
11. The method of claim 1 , wherein LPS signaling is inhibited.
12. The method of claim 1 , wherein LPS induced inflammation is inhibited.
13. The method of claim 1 , wherein the LPS induced inflammation is lung inflammation and the lung inflammation is inhibited.