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 to granulocytic differentiation by dimethyl sulfoxide. The presence of a factor in human serum that caused a similar increase was recently demonstrated. Several observations indicate that the serum factor consists of isoforms of TGFbeta. Heat-treated serum and TGFbeta both resulted in almost-equal-to 10-fold increased 5-LO activity of HL-60 cells, antiserum to TGFbeta neutralized the 5-LO-increasing activity in serum, and physical properties of the serum factor (lipophilic nature, alkaline pI, stability to heat and acid) coincided with those of TGFbeta. The pattern of activity of native and heat-treated sera is compatible with activation of a latent form of TGFbeta in serum. This activity was specific for TGFbeta, since none of several other cytokines could increase 5-LO activity in differentiating HL-60 cells. However, granulocyte/macrophage-colony-stimulating factor (GM-CSF) and tumor necrosis factor a enhanced the effect of TGFbeta. The most prominent effects of TGFbeta, 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, respectively, as judged from Western blots). There was no appreciable effect of TGFbeta, or a combination of TGFbeta and GM-CSF, on 5-LO mRNA expression.