Lipopolysaccharide induces H1 receptor expression and enhances histamine responsiveness in human coronary artery endothelial cells.
Summary Histamine is a well-recognized modulator of vascular inflammation. We have shown that histamine, acting via H1 receptors (H1R), synergizes lipopolysaccharide (LPS)-induced production of prostaglandin I(2) (PGI(2)), PGE(2) and interleukin-6 (IL-6) by endothelial cells. The synergy between histamine and LPS was partly attributed to histamine -induced expression of Toll-like receptor 4 (TLR4). In this study, we examined whether LPS stimulates the H1R expression in human coronary artery endothelial cells (HCAEC) with resultant enhancement of histamine responsiveness. Incubation of HCAEC with LPS (10-1000 ng/ml) resulted in two-fold to fourfold increases in H1R mRNA expression in a time-dependent and concentration-dependent fashion. In contrast, LPS treatment did not affect H2R mRNA expression. The LPS-induced H1R mRNA expression peaked by 4 hr after LPS treatment and remained elevated above the basal level for 20-24 hr. Flow cytometric and Western blot analyses revealed increased expression of H1R protein in LPS-treated cells. The specific binding of [(3)H]pyrilamine to H1R in membrane proteins from LPS-treated HCAEC was threefold higher than the untreated cells. The LPS-induced H1R expression was mediated through TLR4 as gene silencing by TLR4-siRNA and treatment with a TLR4 antagonist inhibited the LPS effect. When HCAEC were pre-treated with LPS for 24 hr, washed and challenged with histamine, 17-, 10- and 15-fold increases in PGI(2), PGE(2) and IL-6 production, respectively, were noted. Histamine-induced enhancement of the synthesis of PGI(2), PGE(2) and IL-6 by LPS-primed HCAEC was completely blocked by an H1R antagonist. The results demonstrate that LPS, through TLR4 activation, up-regulates the expression and function of H1R and amplifies histamine-induced inflammatory responses in HCAEC.
Division of Allergy, Clinical Immunology and Rheumatology, Department of Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Vineesh V
VV
Raveendran
Xiaoyu
X
Tan
Matthew E
ME
Sweeney
Beth
B
Levant
Joyce
J
Slusser
Daniel J
DJ
Stechschulte
Kottarappat N
KN
Dileepan
D015153:Blotting, Western; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology; D015232:Dinoprostone / Q000378:metabolism; D004357:Drug Synergism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D011464:Epoprostenol / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D006632:Histamine / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D011738:Pyrilamine / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011869:Radioligand Assay; D011969:Receptors, Histamine H1 / Q000235:genetics / Q000378:metabolism*; D011970:Receptors, Histamine H2 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014316:Tritium
D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D013449:Sulfonamides; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C507035:ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate; D014316:Tritium; D006632:Histamine; D011464:Epoprostenol; D011738:Pyrilamine; D015232:Dinoprostone
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