Identification of a specific haptoglobin C ‐terminal fragment in arthritic synovial fluid and its effect on interleukin‐6 expression

Summary Haptoglobin ( H p), a major acute‐phase plasma protein, has been found in arthritic synovial fluid ( SF ). However, the function and structural modifications of H p in arthritic SF are unknown. To investigate in vivo generation of modified H p associated with inflammatory disease, we examined a new H p isoform in SF from patients with rheumatoid arthritis ( RA ). Specific H p fragments of 28 000 and 15 000 molecular weight were identified in SF of patients with RA , and the two polypeptides were presumed to be fragments of the H p β‐chain (43 000 MW) produced by cleavage with plasmin. The 15 000 MW fragment, which is a C ‐terminal region of H p, was observed at higher frequency and levels in RA than in osteoarthritis. Plasmin activity was also higher in SF of RA patients. A recombinant 15 000 MW H p fragment up‐regulated interlukin‐6 expression in monocytic cells. These findings indicate that the C ‐terminal H p fragment is generated by plasmin in local inflammatory environments and acts as an inflammatory mediator. They further suggest that a specific H p fragment might be applied as a novel biomarker for the diagnosis and prognosis of inflammatory diseases such as RA .