TIMP1 induces CD44 expression and the activation and nuclear translocation of SHP1 during the late centrocyte/post-germinal center B cell differentiation.

Tissue inhibitor of metalloproteinase-1 (TIMP1) is a survival factor of germinal center (GC) B cells, and its over-expression is correlated with aggressive B cell lymphomas and classical Hodgkin lymphomas. We previously demonstrated that TIMP1 down-regulates B-cell receptor and BCL6, and activates interleukins-6,-10 (ILs)/signal transducer and activator of transcription-3 (STAT3) signaling in GC B cells. The activation of ILs/STAT3 signaling can amplify CD44 function, and vice versa, and induce protein-tyrosine phosphatase SHP1 activity by a negative feedback mechanism. Here, we show that TIMP1 up-regulates cell surface CD44 (standard and variants 3 and 7-10) and induces the activity and nuclear localization of SHP1 in an Epstein Barr virus (EBV)-negative Burkitt lymphoma cell line, the neoplastic counterpart of GC centroblasts. These results suggest that TIMP1 functions as a differentiating and survival factor of GC B cells by modulating CD44 and SHP1 in the late centrocyte/post-GC stage, regardless of EBV infection.