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.
CONCLUSION: 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.