Abstract
Neutrophils play a central role in host defense, inflammation, and tissue injury. Recent findings indicate a novel role for polyisoprenyl phosphates (PIPPs) as natural down-regulatory signals in neutrophils. The relationship between PIPPs and neutrophil early activating signals, such as phosphoinositides, has not been previously determined. Here, we establish presqualene diphosphate (PSDP) as an endogenous PIPP regulator of phosphatidylinositol 3-kinase (PI3K). In human neutrophils, leukotriene B 4 (LTB 4) triggered rapid decreases in PSDP and reciprocal increases in PI3K activity. In addition, PSDP was identified by gas chromatography/mass spectrometry in p110γ-PI3K immunoprecipitates obtained 30 s after LTB 4, indicating a physical interaction between PSDP and PI3K in activated neutrophils. Moreover, PSDP (0.4-800 pmol) directly inhibited recombinant human p110γ-PI3K activity. During an experimental model of lung injury and inflammation, a reciprocal relationship was also present in vivo for lung PSDP and PI3K activity. To investigate its therapeutic potential, we developed a new PSDP structural mimetic that blocked human neutrophil activation and mouse lung PI3K activity and inflammation. Together, our findings indicate that PSDP is an endogenous PI3K inhibitor, and suggest that in inflammatory diseases characterized by excessive neutrophil activation, PIPPs can serve as structural templates in a novel antineutrophil therapeutic strategy to limit tissue injury.
| Original language | English |
|---|---|
| Pages (from-to) | 857-863 |
| Number of pages | 7 |
| Journal | Journal of Experimental Medicine |
| Volume | 203 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2006 Apr 17 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Immunology
Cite this
Regulation of phosphatidylinositol 3-kinase by polyisoprenyl phosphates in neutrophil-mediated tissue injury. / Bonnans, Caroline; Fukunaga, Koichi; Keledjian, Raquel; Petasis, Nicos A.; Levy, Bruce D.
In: Journal of Experimental Medicine, Vol. 203, No. 4, 17.04.2006, p. 857-863.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Regulation of phosphatidylinositol 3-kinase by polyisoprenyl phosphates in neutrophil-mediated tissue injury
AU - Bonnans, Caroline
AU - Fukunaga, Koichi
AU - Keledjian, Raquel
AU - Petasis, Nicos A.
AU - Levy, Bruce D.
PY - 2006/4/17
Y1 - 2006/4/17
N2 - Neutrophils play a central role in host defense, inflammation, and tissue injury. Recent findings indicate a novel role for polyisoprenyl phosphates (PIPPs) as natural down-regulatory signals in neutrophils. The relationship between PIPPs and neutrophil early activating signals, such as phosphoinositides, has not been previously determined. Here, we establish presqualene diphosphate (PSDP) as an endogenous PIPP regulator of phosphatidylinositol 3-kinase (PI3K). In human neutrophils, leukotriene B 4 (LTB 4) triggered rapid decreases in PSDP and reciprocal increases in PI3K activity. In addition, PSDP was identified by gas chromatography/mass spectrometry in p110γ-PI3K immunoprecipitates obtained 30 s after LTB 4, indicating a physical interaction between PSDP and PI3K in activated neutrophils. Moreover, PSDP (0.4-800 pmol) directly inhibited recombinant human p110γ-PI3K activity. During an experimental model of lung injury and inflammation, a reciprocal relationship was also present in vivo for lung PSDP and PI3K activity. To investigate its therapeutic potential, we developed a new PSDP structural mimetic that blocked human neutrophil activation and mouse lung PI3K activity and inflammation. Together, our findings indicate that PSDP is an endogenous PI3K inhibitor, and suggest that in inflammatory diseases characterized by excessive neutrophil activation, PIPPs can serve as structural templates in a novel antineutrophil therapeutic strategy to limit tissue injury.
AB - Neutrophils play a central role in host defense, inflammation, and tissue injury. Recent findings indicate a novel role for polyisoprenyl phosphates (PIPPs) as natural down-regulatory signals in neutrophils. The relationship between PIPPs and neutrophil early activating signals, such as phosphoinositides, has not been previously determined. Here, we establish presqualene diphosphate (PSDP) as an endogenous PIPP regulator of phosphatidylinositol 3-kinase (PI3K). In human neutrophils, leukotriene B 4 (LTB 4) triggered rapid decreases in PSDP and reciprocal increases in PI3K activity. In addition, PSDP was identified by gas chromatography/mass spectrometry in p110γ-PI3K immunoprecipitates obtained 30 s after LTB 4, indicating a physical interaction between PSDP and PI3K in activated neutrophils. Moreover, PSDP (0.4-800 pmol) directly inhibited recombinant human p110γ-PI3K activity. During an experimental model of lung injury and inflammation, a reciprocal relationship was also present in vivo for lung PSDP and PI3K activity. To investigate its therapeutic potential, we developed a new PSDP structural mimetic that blocked human neutrophil activation and mouse lung PI3K activity and inflammation. Together, our findings indicate that PSDP is an endogenous PI3K inhibitor, and suggest that in inflammatory diseases characterized by excessive neutrophil activation, PIPPs can serve as structural templates in a novel antineutrophil therapeutic strategy to limit tissue injury.
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U2 - 10.1084/jem.20052143
DO - 10.1084/jem.20052143
M3 - Article
C2 - 16567384
AN - SCOPUS:33645856488
VL - 203
SP - 857
EP - 863
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 4
ER -