A human anti-inflammatory 5-MER peptide MTADV (methionine-threonine-alanine-aspartic acid-valine) derived from a sequence of a pro-inflammatory CD44 variant was first described by us in Nedvetzki et al., J. Clin. Invest. 111,1211-1220, 2003. A NCBI BLAST RefSeq protein sequence database, that contains at present 81,347 human protein sequences, reveals that only one additional protein contains this unique MTADV sequence of alternating hydrophobic and hydrophilic amino acids. This human peptide displays an efficient anti-inflammatory effect in Inflammatory Bowel Disease (IBD), Rheumatoid Arthritis and Multiple sclerosis mouse models, all share amyloid proteins in the relevant target organs. We show here that the 5-MER peptide, administered after the onset of disease ,either by SC injections or oral delivery, inhibited the pathological activity of two IBD models (TNBS and DSS), as indicated by histopathology analysis (Ameho’s score) or Bioluminescence Imaging, sensing the release of Reactive Oxdative Species (ROS), which reflect colon inflammation (Fig 1). The 5-MER MTADV peptide, while inhibiting chronic inflammation, neither interferes with normal immune responses nor induce neutralizing antibodies. A pull-down experiment with mass spectrometric analysis revealed that the 5-MER peptide specifically binds to serum amyloid A (SAA), a stress pro-inflammatory protein, which generates aggregated amyloid deposits in the IBD colon (de Villiers at al Cytokine 12:1337-1347,2000). Our studies further provide in vitro evidence, strengthened by in vivo experiments, that SAA is a significant target of this pentamer. To this end, the 5-MER peptide (but not the corresponding scrambled peptide) inhibits the release of the pro-inflammatory cytokines IL-6 and IL-1β from SAA-activated fibroblasts. Furthermore, the 5-MER peptide was found to retard the early stages of amyloid-type aggregation of SAA in solution (Fig 2). Adopting the β-sheet conformation, MTADV would display opposing hydrophobic and hydrophilic faces that could interact with the β-sheet-forming amyloidogenic sequences in SAA. This suggests that the mechanism of action for the 5-MER peptide in vivo may depend on its ability to slow the aggregation of SAA, thus reduce its contribution to chronic inflammation. Finally, using bioinformatics and qRT-PCR, we have found the pentamer up-regulates set of genes involved in resistance to chronic inflammations. Hence, our study provides both a new potential drug (MTADV) and a new therapeutic target candidate (SAA) for IBD.