Geranylgeranyl transferase regulates streptococcal M1 protein-induced CXC chemokine formation and neutrophil recruitment in the lung.
Streptococcal toxic shock syndrome is most frequently associated with Streptococcus pyogenes of the M1 serotype. Simvastatin protects against M1 protein-induced acute lung damage, although downstream mechanisms remain elusive. Herein, we hypothesized that geranylgeranylation might regulate proinflammatory effects in M1 protein-induced lung injury. Male C57BL/6 mice received the geranylgeranyl transferase inhibitor, GGTI-2133, before M1 protein injection. Bronchoalveolar fluid and lung tissue were harvested for quantification of neutrophil recruitment, edema, and CXC chemokine formation. Mac-1 expression on neutrophils was quantified by use of flow cytometry. Quantitative reverse transcriptase-polymerase chain reaction was used to determine gene expression of CXC chemokines in alveolar macrophages. GGTI-2133 reduced M1 protein-provoked infiltration of neutrophils, edema, and tissue injury in the lung. Inhibition of geranylgeranyl transferase had no effect on M1 protein-evoked upregulation of Mac-1 on neutrophils. However, geranylgeranyl transferase inhibition completely inhibited pulmonary formation of CXC chemokines in mice exposed to M1 protein. Notably, GGTI-2133 abolished M1 protein-induced gene expression of CXC chemokines in alveolar macrophages. These novel findings indicate that geranylgeranyl transferase is an important regulator of neutrophil recruitment and CXC chemokine production in the lung. Thus, targeting geranylgeranyl transferase might be a potent way to ameliorate streptococcal M1 protein-triggered acute lung injury.
Department of Clinical Sciences, Section for Surgery, Malmö University Hospital, Malmö, Sweden.
Songen
S
Zhang
Milladur
M
Rahman
Bengt
B
Jeppsson
Heiko
H
Herwald
Henrik
H
Thorlacius
D055371:Acute Lung Injury / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; D019743:Chemokines, CXC / Q000096:biosynthesis*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D007093:Imidazoles / Q000627:therapeutic use; D007930:Leucine / Q000031:analogs & derivatives / Q000627:therapeutic use; D008168:Lung / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000096:biosynthesis; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009281:Naphthalenes / Q000627:therapeutic use; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000502:physiology; D009504:Neutrophils / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; D019743:Chemokines, CXC; D004791:Enzyme Inhibitors; C547856:GGTI-2133; D007093:Imidazoles; D016177:Macrophage-1 Antigen; D009281:Naphthalenes; C014689:streptococcal M protein; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D007930:Leucine