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.
Kim
Young-Sik
YS
Department of Pathology, Korea University Ansan Hospital, 516 Gojan-1 Dong, Danwon-Gu, Gyeonggi-Do, Ansan 425-707, Republic of Korea. apysk@korea.ac.kr
Seo
Dong-Wan
DW
Kong
Su-Kang
SK
Lee
Ju-Han
JH
Lee
Eung-Seok
ES
Stetler-Stevenson
Maryalice
M
Stetler-Stevenson
William G
WG
D021581:Active Transport, Cell Nucleus; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D020895:Enterocytes / Q000166:cytology*; D018858:Germinal Center / Q000166:cytology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis / Q000096:biosynthesis*; D050835:Interferon Regulatory Factors / Q000032:analysis; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000032:analysis / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis / Q000502:physiology*; D000099218:Interferon Regulatory Factor-4
D018960:Hyaluronan Receptors; D050835:Interferon Regulatory Factors; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D019715:Tissue Inhibitor of Metalloproteinase-1; D000099218:Interferon Regulatory Factor-4; C497483:CD44 protein, human