Tissue inhibitor of metalloproteinases 1 regulation of interleukin-10 in B-cell differentiation and lymphomagenesis.
Tissue inhibitors of metalloproteinases (TIMPs), first described as specific inhibitors of matrix metalloproteinases, have recently been shown to exert growth factor activities. It was previously demonstrated that TIMP-1 inhibits apoptosis in germinal center B cells and induces further differentiation. Interleukin-10 (IL-10) is reported as a vital factor for the differentiation and survival of germinal center B cells and is also a negative prognostic factor in non-Hodgkin lymphoma (NHL). However, the mechanism of IL-10 activity in B cells and the regulation of its expression are not well understood. IL-10 has been shown to up-regulate TIMP-1 in tissue macrophages, monocytes, and prostate cancer cell lines, but IL-10 modulation of TIMP-1 in B cells and the effect of TIMP-1 on IL-10 expression has not been previously studied. It was found that TIMP-1 expression regulates IL-10 levels in B cells and that TIMP-1 mediates specific B-cell differentiation steps. TIMP-1 inhibition of apoptosis is not IL-10 dependent. TIMP-1 expression in B-cell NHL correlates closely with IL-10 expression and with high histologic grade. Thus, TIMP-1 regulates IL-10 expression in B-cell NHL and, through the inhibition of apoptosis, appears responsible for the negative prognosis associated with IL-10 expression in these tumors.
Flow Cytometry Unit and the Extracellular Matrix Pathology Section, Laboratory of Pathology, and the Biostatistics and Data Management Section, Division of Clinical Sciences, National Cancer Institute, Bethesda, MD 20892, USA.
L
L
Guedez
A
A
Mansoor
B
B
Birkedal-Hansen
M S
MS
Lim
P
P
Fukushima
D
D
Venzon
W G
WG
Stetler-Stevenson
M
M
Stetler-Stevenson
D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D005629:Frozen Sections; D006801:Humans; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D008228:Lymphoma, Non-Hodgkin / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D012313:RNA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
D019715:Tissue Inhibitor of Metalloproteinase-1; D016753:Interleukin-10; D012313:RNA