TRANSFORMING GROWTH-FACTOR-BETA UP-REGULATES 5-LIPOXYGENASE ACTIVITY DURING MYELOID CELL MATURATION

Transforming growth factor beta (TGFbeta) increased the arachidonate 5 -lipoxygenase (5-LO; EC 1.13. 11.34) activity in HL-60 cells induced t o granulocytic differentiation by dimethyl sulfoxide. The presence of a factor in human serum that caused a similar increase was recently de monstrated. Several observations indicate that the serum factor consis ts of isoforms of TGFbeta. Heat-treated serum and TGFbeta both resulte d in almost-equal-to 10-fold increased 5-LO activity of HL-60 cells, a ntiserum to TGFbeta neutralized the 5-LO-increasing activity in serum, and physical properties of the serum factor (lipophilic nature, alkal ine pI, stability to heat and acid) coincided with those of TGFbeta. T he pattern of activity of native and heat-treated sera is compatible w ith activation of a latent form of TGFbeta in serum. This activity was specific for TGFbeta, since none of several other cytokines could inc rease 5-LO activity in differentiating HL-60 cells. However, granulocy te/macrophage-colony-stimulating factor (GM-CSF) and tumor necrosis fa ctor a enhanced the effect of TGFbeta. The most prominent effects of T GFbeta, whether alone or together with GM-CSF, were observed for 5-LO activity in intact cells (10-fold or 30-fold induction, respectively). 5-LO protein levels were less affected (up to 2- or 5-fold, respectiv ely, as judged from Western blots). There was no appreciable effect of TGFbeta, or a combination of TGFbeta and GM-CSF, on 5-LO mRNA express ion.