Interactions between lipoxin A4, the stable analogue 16-phenoxy-lipoxin A4 and leukotriene B4 in cytokine generation by human monocytes.
Lipoxins display both stimulatory and inhibitory actions with leucocytes that are cell-type dependent. We tested whether lipoxin A4 (LXA4) and its stable synthetic analogue 16-phenoxy-17-18,19,20-tetranor-lipoxin-A4 (16-phe-LXA4) modulated the ability of human blood monocytes (MO) to express mRNA and proteins for interleukin-1beta (IL-1beta), IL-6 and IL-1 receptor antagonist (IL-1Ra) in vitro and compared their actions with lipopolysaccharide (LPS) and leukotriene B4 (LTB4). 16-phe-LXA4, LPS and LTB4, but not LXA4, induced gene expression of IL-1beta in MO. IL-1beta protein synthesis increased by LPS (1500-fold), LTB4 (280-fold) and 16-phe-LXA4 (30-fold). Although the IL-1Ra gene was constitutively activated, mRNA concentration not affected by any of the stimulants, IL-Ra protein synthesis was increased by LPS (with 74%), 16-phe-LXA4 (35%) and LTB4 (20%), but not by LXA4. Each of these stimuli upregulated the IL-6 gene. Increases of IL-6 protein were 3000-fold for LPS, threefold for 16-phe-LXA4, eightfold for LXA(4 and) twofold for LTB4. Prior exposure of MO to 16-phe-LXA4, but not LXA4, reduced LTB4 induced synthesis of IL-1beta with 66%, IL-6 with 20% and IL-1Ra with 29%. Thus, a stable LXA analogue, that resists rapid inactivation by monocytes, displays novel actions in cytokine generation, intimately involved in the regulation of inflammation.
Department of Medicine, Karolinska Institutet at Stockholm Söder Hospital, Stockholm, Sweden.
P
P
Andersson
C N
CN
Serhan
N A
NA
Petasis
J
J
Palmblad
D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D007975:Leukotriene B4 / Q000378:metabolism*; D044045:Lipoxins / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000096:biosynthesis / Q000235:genetics
D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D044045:Lipoxins; D017472:Receptors, Interleukin-1; C040527:lipoxin A4; D007975:Leukotriene B4