Reciprocal Regulation of LTA ₄ Hydrolase Expression in Human Monocytes by γ-Interferon and Interleukins 4 and 13: Potential Relevance to Leukotriene Regulation in Glomerular Disease

Abstract

Background/Aims: Leukotriene A₄ (LTA₄) hydrolase catalyzes the final step in the synthesis of leukotriene B₄ (LTB₄). TH-1- and TH-2-derived cytokines may regulate LTB₄ synthesis by monocytes through their actions on the expression of LTA₄ hydrolase. Methods: Freshly isolated monocytes were incubated with pro- and anti-inflammatory cytokines for 36 h. mRNA expression was determined by Northern blot, protein expression was determined by Western blot and LTB₄ synthesis was determined by ELISA. Results: Interferon-γ (a TH-2-derived cytokine) increased significantly LTA₄ hydrolase mRNA expression, whereas interleukin (IL)-4 and IL-13 (both TH-2-derived cytokines) decreased LTA₄ hydrolase mRNA expression in these cells. The same effects were seen on the expression of immunoreactive LTA₄ hydrolase after incubating the monocytes with either TH-1- or TH-2-derived cytokines. The monocyte-derived cytokine IL-1β did not show any significant effect on LTA₄ hydrolase mRNA expression. When LTB₄ release was measured, both IL-1β and interferon-γ significantly increased LTB₄ production by monocytes, while TH-2 cytokines (IL-4 and IL-13) decreased it. Conclusion: The opposing effects of TH-1- and TH-2-derived cytokines on the expression of LTA₄ hydrolase mRNA may regulate LTB₄ synthesis by monocytes during inflammation.