Tissue inhibitor of metalloproteinases 1 regulation of interleukin-10 in B-cell differentiation and lymphomagenesis

Tissue inhibitors of metalloproteinases (TIMPs), first described as specifi c inhibitors of matrix metalloproteinases, have recently been shown to exer t growth factor activities. It was previously demonstrated that TIMP-1 inhi bits apoptosis in germinal center B cells and induces further differentiati on. Interleukin-10 (IL-10) is reported as a vital factor for the differenti ation and survival of germinal center B cells and is also a negative progno stic 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 under stood. IL-10 has been shown to up-regulate TIMP-1 in tissue macrophages, mo nocytes, 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 previousl y 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-ce ll NHL correlates closely with IL-10 expression and with high histologic gr ade. Thus, TIMP-1 regulates IL-10 expression in B-cell NHL and, through the inhibition of apoptosis, appears responsible for the negative prognosis as sociated with IL-10 expression in these tumors. (Blood. 2001; 97:1796-1802) (C) 2001 by The American Society of Hematology.