Reciprocal regulation of LTA(4) hydrolase expression in human monocytes by gamma-interferon and interleukins 4 and 13: potential relevance to leukotriene regulation in glomerular disease.
OBJECTIVE
Leukotriene A(4) (LTA(4)) hydrolase catalyzes the final step in the synthesis of leukotriene B(4) (LTB(4)). TH-1- and TH-2-derived cytokines may regulate LTB(4) synthesis by monocytes through their actions on the expression of LTA(4) 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 LTB(4) synthesis was determined by ELISA.


RESULTS
Interferon-gamma (a TH-2-derived cytokine) increased significantly LTA(4) hydrolase mRNA expression, whereas interleukin (IL)-4 and IL-13 (both TH-2-derived cytokines) decreased LTA(4) hydrolase mRNA expression in these cells. The same effects were seen on the expression of immunoreactive LTA(4) hydrolase after incubating the monocytes with either TH-1- or TH-2-derived cytokines. The monocyte-derived cytokine IL-1 beta did not show any significant effect on LTA(4) hydrolase mRNA expression. When LTB(4) release was measured, both IL-1 beta and interferon-gamma significantly increased LTB(4) production by monocytes, while TH-2 cytokines (IL-4 and IL-13) decreased it.


CONCLUSIONS
The opposing effects of TH-1- and TH-2-derived cytokines on the expression of LTA(4) hydrolase mRNA may regulate LTB(4) synthesis by monocytes during inflammation.
Center for Glomerulonephritis, Renal Division, Emory University, Atlanta, GA 30033, USA. amonter@emory.edu
A
A
Montero
G M
GM
Nassar
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Uda
K A
KA
Munger
K F
KF
Badr
D015152:Blotting, Northern; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D004851:Epoxide Hydrolases / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic; D005921:Glomerulonephritis / Q000201:enzymology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D018793:Interleukin-13 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D007975:Leukotriene B4 / Q000096:biosynthesis*; D009000:Monocytes / Q000201:enzymology*; D012333:RNA, Messenger / Q000032:analysis
D018793:Interleukin-13; D012333:RNA, Messenger; D007975:Leukotriene B4; D015847:Interleukin-4; D007371:Interferon-gamma; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase