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Blood, 15 March 2001, Vol. 97, No. 6, pp. 1796-1802
IMMUNOBIOLOGY
Tissue inhibitor of metalloproteinases 1 regulation of
interleukin-10 in B-cell differentiation and lymphomagenesis
Liliana Guedez,
Adnan Mansoor,
Bente Birkedal-Hansen,
Megan S. Lim,
Paula Fukushima,
David Venzon,
William G. Stetler-Stevenson, and
Maryalice Stetler-Stevenson
From the 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.
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.
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