Interleukin-18 Mediates Immune Responses to Campylobacter jejuni Infection in Gnotobiotic Mice.
BACKGROUND
Human Campylobacter jejuni infections are progressively rising worldwide. Information about the molecular mechanisms underlying campylobacteriosis, however, are limited. In the present study we investigated whether cytokines such as IL-23, IL-22 and IL-18, which share pivotal functions in host immunity, were involved in mediating intestinal and systemic immunopathological responses upon C. jejuni infection.


RESULTS
To assure stable infection, gnotobiotic (i.e. secondary abiotic) IL-23p19-/-, IL-22-/- and IL-18-/- mice were generated by broad-spectrum antibiotic treatment. Following peroral C. jejuni strain 81-176 infection, mice of all genotypes harbored comparably high pathogenic loads in their intestines. As compared to wildtype controls, however, IL-18-/- mice displayed less distinct C. jejuni induced sequelae as indicated by less pronounced large intestinal shrinkage and lower numbers of apoptotic cells in the colonic epithelial layer at day 8 postinfection (p.i.). Furthermore, lower colonic numbers of adaptive immune cells including regulatory T cells and B lymphocytes were accompanied by less distinct secretion of pro-inflammatory cytokines such as TNF and IFN-γ and lower IL-17A mRNA expression levels in colonic ex vivo biopsies of infected IL-18-/- as compared to wildtype mice. Upon C. jejuni infection, colonic IL-23p19 expression was up-regulated in IL-18-/- mice only, whereas IL-22 mRNA levels were lower in uninfected and infected IL-23p19-/- as well as infected IL-18-/- as compared to respective wildtype control mice. Remarkably, not only intestinal, but also systemic infection-induced immune responses were less pronounced in IL-18-/- mice as indicated by lower TNF, IFN-γ and IL-6 serum levels as compared to wildtype mice.


CONCLUSIONS
We here show for the first time that IL-18 is essentially involved in mediating C. jejuni infection in the gnotobiotic mouse model. Future studies need to further unravel the underlying regulatory mechanisms orchestrating pathogen-host interaction.
Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Berlin, Germany.
Stefan
S
Bereswill
Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Berlin, Germany.
Marie E
ME
Alutis
Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Berlin, Germany.
Ursula
U
Grundmann
Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Berlin, Germany.
André
A
Fischer
Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Berlin, Germany.
Ulf B
UB
Göbel
Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Berlin, Germany.
Markus M
MM
Heimesaat
D000818:Animals; D017209:Apoptosis; D058491:Bacterial Load / Q000276:immunology; D018988:Bacterial Translocation; D001706:Biopsy; D002169:Campylobacter Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016123:Campylobacter jejuni / Q000254:growth & development / Q000276:immunology*; D049109:Cell Proliferation; D015169:Colony Count, Microbial; D005260:Female; D005786:Gene Expression Regulation; D005856:Germ-Free Life / Q000276:immunology*; D018836:Inflammation Mediators / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D053760:Interleukin-23 Subunit p19 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D007413:Intestinal Mucosa / Q000473:pathology; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000097043:Interleukin-22
D018836:Inflammation Mediators; D020381:Interleukin-17; D020382:Interleukin-18; D053583:Interleukin-1beta; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D012333:RNA, Messenger; D000097043:Interleukin-22