Novel mechanism of C-reactive protein for enhancing mouse liver innate immunity.
Although C-reactive protein (CRP) is a representative acute-phase protein produced by hepatocytes, the role of CRP in liver innate immunity remains unclear. Using C57BL/6 mice, the present study investigated how CRP affects the functions of liver macrophages, Kupffer cells, and natural killer / natural killer T (NK/NKT) cells under various conditions, including Escherichia coli infection, septic shock, and multiorgan dysfunction induced by interleukin (IL)-12/lipopolysaccharide (LPS) (generalized Shwartzman reaction [GSR]), and LPS-induced lethal hepatitis in Propionibacterium acnes-primed mice. When mice were challenged with a lethal dose of E. coli, synthetic CRP peptide decreased the mortality without decreasing serum tumor necrosis factor (TNF), presumably by enhancing the phagocytic activity of Kupffer cells. Synthetic CRP greatly decreased the production of TNF and reactive oxygen species from Kupffer cells and thereby rescued mice after lethal LPS challenge. CRP also decreased the mortality from GSR and lethal hepatitis by inhibiting TNF production from Kupffer cells, especially phagocytosing Kupffer cells. However, interferon-gamma production from NK/NKT cells was generally not so affected. CRP reportedly binds to FcgammaRI and FcgammaRII, and the injection of anti-FcgammaRII/III Ab into mice abrogated TNF production from, but increased the phagocytic activity of, Kupffer cells. Furthermore, CRP pretreatment restored the decreased phagocytic activity of Kupffer cells in burn-injured mice and decreased TNF production by Kupffer cells and thereby inhibited mortality after sublethal E. coli infection. If CRP was injected into mice at 1 hour after lethal E. coli challenge, it slightly but significantly increased the survival rate.


CONCLUSIONS
CRP thus enhances the phagocytosis of Kupffer cells but decreases their TNF production in a complex manner in which the pathway by way of FcgammaRII may be involved.
Inatsu
Akihito
A
Department of Laboratory Medicine, National Defense Medical College Hospital, Saitama, Japan.
Kinoshita
Manabu
M
Nakashima
Hiroyuki
H
Shimizu
Jun
J
Saitoh
Daizoh
D
Tamai
Seiichi
S
Seki
Shuhji
S
D000818:Animals; D002097:C-Reactive Protein / Q000502:physiology*; D006505:Hepatitis / Q000276:immunology*; D007113:Immunity, Innate; D007694:Killer Cells, Natural / Q000276:immunology*; D007728:Kupffer Cells / Q000276:immunology*; D008099:Liver / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
D002097:C-Reactive Protein