The inter-alpha-trypsin inhibitor (ITI) family is a group of structurally related plasma serine protease inhibitors synthesized in the liver and built up from different combinations of three highly homologous heavy chains (ITI-HI, ITI-H2 and ITI-H3) and one light chain (Bikunin). Another member of the ITI family, ITI-H4, harbors a proline-rich region (PRR) in its C-terminus. ITI is a glycoprotein composed of three polypeptides linked by chondroitin sulphate: two heavy chains, ITI-H1 and ITI-H2, and Bikunin. Bikunin confers the protease-inhibitor function of ITI. The heavy chains of the ITI family, designated as SHAPs (for serum-derived hyaluronan-associated proteins), bind covalently to hyaluronic acid (HA), resulting in pericellular matrix stabilization. While the ITI family is primarily composed of multi-polypeptide molecules, ITI-H4 is a single chain molecule. Unlike other ITI family members, the gene transcriptions and products for rat and human ITI-H4 demonstrate marked differences, suggesting possible species-specific functions for ITI-H4. The gene encoding human ITI-H4 maps to chromosome 3p21.1.