Lipophosphoglycan from Leishmania suppresses agonist-induced interleukin 1 beta gene expression in human monocytes via a unique promoter sequence.
Leishmania are parasites that survive within macrophages by mechanism(s) not entirely known. Depression of cellular immunity and diminished production of interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha are potential ways by which the parasite survives within macrophages. We examined the mechanism(s) by which lipophosphoglycan (LPG), a major glycolipid of Leishmania, perturbs cytokine gene expression. LPG treatment of THP-1 monocytes suppressed endotoxin induction of IL-1 beta steady-state mRNA by greater than 90%, while having no effect on the expression of a control gene. The addition of LPG 2 h before or 2 h after endotoxin challenge significantly suppressed steady-state IL-1 beta mRNA by 90% and 70%, respectively. LPG also inhibited tumor necrosis factor alpha and Staphylococcus induction of IL-1 beta gene expression. The inhibitory effect of LPG is agonist-specific because LPG did not suppress the induction of IL-1 beta mRNA by phorbol 12-myristate 13-acetate. A unique DNA sequence located within the -310 to -57 nucleotide region of the IL-1 beta promoter was found to mediate LPG's inhibitory activity. The requirement for the -310 to -57 promoter gene sequence for LPG's effect is demonstrated by the abrogation of LPG's inhibitory activity by truncation or deletion of the -310 to -57 promoter gene sequence. Furthermore, the minimal IL-1 beta promoter (positions -310 to +15) mediated LPG's inhibitory activity with dose and kinetic profiles that were similar to LPG's suppression of steady-state IL-1 beta mRNA. These findings delineated a promoter gene sequence that responds to LPG to act as a "gene silencer", a function, to our knowledge, not previously described. LPG's inhibitory activity for several mediators of inflammation and the persistence of significant inhibitory activity 2 h after endotoxin challenge suggest that LPG has therapeutic potential and may be exploited for therapy of sepsis, acute respiratory distress syndrome, and autoimmune diseases.
Hatzigeorgiou
D E
DE
Division of International Medicine and Infectious Diseases, Cornell University Medical College, New York, NY 10021, USA.
Geng
J
J
Zhu
B
B
Zhang
Y
Y
Liu
K
K
Rom
W N
WN
Fenton
M J
MJ
Turco
S J
SJ
Ho
J L
JL
D000818:Animals; D002478:Cells, Cultured; D004731:Endotoxins / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D006028:Glycosphingolipids / Q000494:pharmacology*; D006801:Humans; D007375:Interleukin-1 / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D007891:Leishmania / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*
D004731:Endotoxins; D006028:Glycosphingolipids; D007375:Interleukin-1; C008290:lipophosphonoglycan