IL-12p40-dependent agonistic effects on the development of protective innate and adaptive immunity against Salmonella enteritidis.
To study a potential IL-12p40-dependent but IL-12p75-independent agonistic activity regulating the immune response against Salmonella Enteritidis, the course of infection in IL-12p35-deficient mice (IL-12p35(-/-), capable of producing IL-12p40) was compared with that of IL-12p40(-/-) mice. Mice lacking IL-12p40 revealed a higher mortality rate and higher bacterial organ burden than mice capable of producing IL-12p40. This phenotype was found in both genetically susceptible (BALB/c, Ity(s)) and resistant mice (129Sv/Ev, Ity(r)) indicating Ity-independent mechanisms. The more effective control of bacteria in the IL-12p35(-/-) mice was associated with elevated serum IFN-gamma and TNF-alpha levels. In contrast, IL-12p40(-/-) mice showed reduced IFN-gamma production, which was associated with significantly elevated serum IgE levels. Early during infection (days 3 and 4 postinfection), as well as late (day 20 postinfection), the number of infected phagocytes was strongly increased in the absence of IL-12p40 indicating impaired bactericidal activity when IL-12p40 was missing. Liver histopathology revealed a decreased number of mononuclear granulomas in IL-12p40(-/-) mice. Depletion of CD4(+) or CD8(+) T lymphocytes in vivo suggested that both T cell subpopulations contribute to the IL-12p40-dependent protective functions. Analysis of IL-12p40 vs IL-23p19 mRNA expression revealed an up-regulation of only IL-12p40 mRNA during Salmonella infection. Together these data indicate that IL-12p40 can induce protective mechanisms during both the innate and the adaptive type 1 immune response in Salmonella infection. This novel activity of IL-12p40 complements the well described dominant and essential role of IL-12p75 in protective immunity to Salmonella infection.
Lehmann
J
J
Institute of Immunology, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany.
Bellmann
S
S
Werner
C
C
Schröder
R
R
Schütze
N
N
Alber
G
G
D000818:Animals; D006099:Granuloma / Q000517:prevention & control; D007371:Interferon-gamma / Q000097:blood; D018664:Interleukin-12 / Q000235:genetics / Q000502:physiology*; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000235:genetics; D008099:Liver / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D010586:Phagocytes / Q000502:physiology; D021122:Protein Subunits; D012333:RNA, Messenger / Q000032:analysis; D012481:Salmonella Infections, Animal / Q000276:immunology*; D012477:Salmonella enteritidis / Q000276:immunology*; D013154:Spleen / Q000382:microbiology; D018417:Th1 Cells / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
C508841:Il23a protein, mouse; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D021122:Protein Subunits; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma