Scientists Report New Finding in Development of B Cells

National Cancer Institute
Thursday, 15 March 2001

In the early 1990s, scientists reported that IL-10, a signaling protein excreted by activated immune cells, was essential for the maturation of B lymphocytes. That is, add IL-10 in culture, and naive, undifferentiated B cells mature; deprive the cells of the protein, and no differentiation occurs.

But, as often happens in science, even the most straightforward discoveries turn out not to be so straightforward. In the latest issue of the journal Blood*, scientists report for the first time that another protein called TIMP-1 seems to switch on the expression of IL-10 in normal B cells and B-cell non-Hodgkin lymphoma.

Maryalice Stetler-Stevenson, Ph.D., a scientist at the National Cancer Institute and senior author on the paper, said this finding is noteworthy because many previous studies of IL-10 almost certainly involved cells and/or serum that contained TIMP-1. "Perhaps some of the biological effects that have been associated with IL-10 are, in fact, driven by TIMP-1," she said. "Until now, there was no reason even to consider this possibility."

Stetler-Stevenson noted that the finding could have important clinical implications. She said the group showed that high TIMP-1 levels were found in severe, or high-grade, B-cell lymphomas, while the protein was undetectable or nearly absent in the low-grade cancers. The authors say this further supports previous reports of poor prognoses for B-cell non-Hodgkin lymphomas that express high levels of IL-10.

B lymphocytes are one member of the body's immune system, an integrated network of cells, each with its own unique tasks within the system, that attack disease-causing viruses, bacteria, and other pathogens. Among immunologists, B lymphocytes are best known for secreting antibodies, small, individualized proteins that attach to specific pathogens and mark them, like red flags, for further attack.

However, before antibodies can be produced, naive B lymphocytes stored in the lymph node must differentiate and mature. In most laboratories, studying this process has meant exposing B lymphocytes in culture to IL-10, and, given IL-10's reputation as a potent signaling protein, most scientists assumed that's where the story ended.

But, in the late 1990s, Stetler-Stevenson and colleagues eventually began to question this assumption based on their studies of TIMP-1, an inhibitory enzyme that has also been shown to signal immune cells to grow. In a series of experiments, they reported that TIMP-1 levels were high in activated normal B lymphocytes and Burkitt's lymphoma, a B-cell cancer. Then, in 1998, the laboratory reported that the lymphoma cell lines also seemed to mature when TIMP-1 was expressed. Interestingly, the data indicated that the TIMP-1-exposed cells also expressed a surface protein that previous work had shown must be present before IL-10 can be activated.

This raised the question of which protein was really running the show: TIMP-1 or IL-10? To find out, the scientists performed a series of experiments with established Burkitt's lymphoma cell lines. The scientists found that all of the cell lines that expressed TIMP-1 also expressed IL-10. But in those lacking TIMP-1, no IL-10 was produced. "It is also interesting that the expression of IL-10 was proportional to the level of TIMP-1 found in the cell," said Liliana Guedez, Ph.D., an NCI scientist and lead author on the study.

According to Guedez, she and her colleagues are now following up the current finding with additional studies of TIMP-1's control of other interleukins, or ILs, that are involved in B-cell maturation and survival. They are also exploring the correlation between high and low TIMP-1 levels in lymphoma.

*The article is entitled, "Tissue inhibitor of metalloproteinases 1 regulation of interleukin-10 in B-cell differentiation and lymphomagenesis." The authors are Liliana Guedez, Adnan Mansoor, Bente Birkedal-Hansen, Megan S. Lim, Paula Fukishima, David Venzon, William G. Stetler-Stevenson, and Maryalice Stetler-Stevenson.

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