Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Aberrant inflammation probably results from aberrant regulation of the molecules that mediate inflammation; the actual molecules mediating inflammation –

• chemokines,
• cytokines, and
• growth factors and their receptors –
  • would appear to be normal in their chemical structure.

If faulty regulation is indeed the problem,

• a reasonable approach to alleviating inflammatory diseases might be to influence the interactions
• within the network of connectivity of the disease-associated proteins (DAPs).

Aberrant inflammation appears to be a pathogenic factor in autoimmune diseases and other noxious inflammatory

conditions in which the inflammatory process

1. is misapplied,
2. exaggerated,
3. recurrent or chronic.

The protein molecules involved in pathogenic inflammation—
disease-associated proteins (DAP )—

1. chemokines,
2. cytokines, and
3. growth factors and their receptors,

• appear normal; their networks of interaction are at fault.

This study demonstrates a new

• approach to network regulation of inflammation based on peptide sequence motifs
• shared by the second extra-cellular loop (EC L2) of different chemokine receptors;
• previously known chemokine receptor binding sites have not involved the EC L2 loop.

These motifs of 9 amino acids, which were detected by sequence alignment, manifest very low E-values

• compared with slightly modified sequence variations,
• indicating that they were not likely to have evolved by chance.

To test whether this shared sequence network (SSN) might serve a regulatory function,

• theysynthesized 9-amino acid SSN peptides from the EC L2 loops of three different chemokine receptors.

Theye administered these peptides to rats during the

• induction of a model of autoimmune arthritis.

Two of the peptides significantly downregulated the arthritis; one of the peptides

• synergized with non-specific anti-inflammatory treatment with dexamethasone.

These findings suggest that

• the SSN peptide motif reported here is likely to have adaptive value in controlling inflammation.
• detection of SSN motif peptides could provide a network-based approach to immune modulation.