Interferon consensus sequence binding protein confers resistance against Yersinia enterocolitica.
Interferon consensus sequence binding protein (ICSBP)-deficient mice display enhanced susceptibility to intracellular pathogens. At least two distinct immunoregulatory defects are responsible for this phenotype. First, diminished production of reactive oxygen intermediates in macrophages results in impaired intracellular killing of microorganisms. Second, defective early interleukin-12 (IL-12) production upon microbial challenge leads to a failure in gamma interferon (IFN-gamma) induction and subsequently in T helper 1 immune responses. Here, we investigated the role of ICSBP in resistance against the extracellular bacterium Yersinia enterocolitica. ICSBP(-/-) mice failed to produce IL-12 and IFN-gamma, but also IL-4, after Yersinia challenge. In addition, granuloma formation was highly disturbed in infected ICSBP(-/-) mice, leading to multiple necrotic abscesses in affected organs. Consequently, ICSBP(-/-) mice rapidly succumbed to acute Yersinia infection. In vitro treatment of spleen cells from ICSBP(-/-) mice with recombinant IL-12 (rIL-12) or rIL-18 in combination with a second stimulus resulted in IFN-gamma induction. In experimental therapy of infected ICSBP(-/-) mice, we observed that administration of rIL-12 induced IFN-gamma production which was associated with improved resistance to Yersinia. In contrast, treatment with rIL-18 failed to enhance endogenous IFN-gamma production but nevertheless reduced bacterial burden in ICSBP(-/-) mice. Although cytokine therapy with rIL-12 or rIL-18 ameliorated the course of Yersinia infection in ICSBP(-/-) mice, both cytokines failed to completely restore impaired immunity. Taken together, the results indicate that the transcription factor ICSBP is essential for efficient host immune defense against Yersinia. These results are important for understanding the complex host immune responses in bacterial infections.
Hein
J
J
Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, Ludwig-Maximilians-Universität, Munich, Germany.
Kempf
V A
VA
Diebold
J
J
Bücheler
N
N
Preger
S
S
Horak
I
I
Sing
A
A
Kramer
U
U
Autenrieth
I B
IB
D000818:Animals; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis / Q000494:pharmacology; D020382:Interleukin-18 / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012097:Repressor Proteins / Q000502:physiology*; D015009:Yersinia Infections / Q000276:immunology*; D015008:Yersinia enterocolitica / Q000276:immunology*; D000099185:Interferon Regulatory Factor-8
D050835:Interferon Regulatory Factors; D007371:Interferon-gamma; D018664:Interleukin-12; D020382:Interleukin-18; D012097:Repressor Proteins; D000099185:Interferon Regulatory Factor-8