Heterotrimeric G proteins physically associated with the lipopolysaccharide receptor CD14 modulate both in vivo and in vitro responses to lipopolysaccharide.
Septic shock induced by lipopolysaccharide (LPS) triggering of cytokine production from monocytes/macrophages is a major cause of morbidity and mortality. The major monocyte/macrophage LPS receptor is the glycosylphosphatidylinositol (GPI)-anchored glycoprotein CD14. Here we demonstrate that CD14 coimmunoprecipitates with Gi/Go heterotrimeric G proteins. Furthermore, we demonstrate that heterotrimeric G proteins specifically regulate CD14-mediated, LPS-induced mitogen-activated protein kinase (MAPK) activation and cytokine production in normal human monocytes and cultured cells. We report here that a G protein binding peptide protects rats from LPS-induced mortality, suggesting a functional linkage between a GPI-anchored receptor and the intracellular signaling molecules with which it is physically associated.
Solomon
K R
KR
Infectious Disease Unit, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Kurt-Jones
E A
EA
Saladino
R A
RA
Stack
A M
AM
Dunn
I F
IF
Ferretti
M
M
Golenbock
D
D
Fleisher
G R
GR
Finberg
R W
RW
D000818:Animals; D002460:Cell Line; D019204:GTP-Binding Proteins / Q000302:isolation & purification / Q000502:physiology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000187:drug effects / Q000302:isolation & purification / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology* / Q000633:toxicity; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010455:Peptides; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012772:Shock, Septic / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014162:Transfection; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D014862:Wasp Venoms / Q000494:pharmacology / Q000627:therapeutic use
D036341:Intercellular Signaling Peptides and Proteins; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D010455:Peptides; D011993:Recombinant Fusion Proteins; D010566:Virulence Factors, Bordetella; D014862:Wasp Venoms; C037500:mastoparan; D019204:GTP-Binding Proteins