IFN-GAMMA ABROGATES IL-7-DEPENDENT PROLIFERATION IN PRE-B CELLS, COINCIDING WITH ONSET OF APOPTOSIS

These studies investigated the mechanism by which interferon-gamma (IF N-gamma) inhibits the interleukin-7 (IL-7)-dependent proliferation of BALB/c bone marrow B-cell precursors in vitro. Low concentrations (1 U /ml) of recombinant murine IFN-gamma (rmIFN-gamma) caused a similar to 80% suppression of IL-7 colony-forming units (CFU) formation in semi- solid media, in part through a direct affect on isolated B220(+) pre-B cells. IFN-gamma did not induce apoptosis in small resting pre-B cell s in BALB/c bone marrow. There was no difference in the proportion of apoptotic B220(+) pre-B cells in IFN-gamma-treated cultures compared t o cultures treated with IL-7 alone. However, IL-7-responsive pre-B cel ls generated from bone marrow had a 30-50% loss in cells in S+G(2)/M p hases of the cell cycle and an increase of up to twice as many in apop totic cells within 48 hr of exposure to IFN-gamma. Notably, expression of the tyrosine phosphatase B220 was increased in the IFN-gamma-treat ed pre-B cells. Interestingly, although there was no substantial chang e in IL-7 receptor mRNA expression upon IFN-gamma treatment, a small d ecrease in binding of biotinylated IL-7 to IFN-gamma-treated pre-B cel ls was observed. These results suggest that IFN-gamma inhibits IL-7 re sponsiveness in pre-B cells, resulting in a subtle down-regulation of IL-7 binding, inhibition of proliferation and, ultimately, apoptosis.