Salmonella induced IL-23 and IL-1beta allow for IL-12 production by monocytes and Mphi1 through induction of IFN-gamma in CD56 NK/NK-like T cells.
BACKGROUND
The type-1 cytokine pathway plays a pivotal role in immunity against intracellular bacterial pathogens such as Salmonellae and Mycobacteria. Bacterial stimulation of pattern recognition receptors on monocytes, macrophages and dendritic cells initiates this pathway, and results in the production of cytokines that activate lymphocytes to produce interferon (IFN)-gamma. Interleukin (IL)-12 and IL-23 are thought to be the key cytokines required for initiating a type-1 cytokine immune response to Mycobacteria and Salmonellae. The relative contribution of IL-23 and IL-12 to this process is uncertain.


RESULTS
We show that various TLR agonists induce the production of IL-23 but not IL-12 in freshly isolated human monocytes and cultured human macrophages. In addition, type 1 pro-inflammatory macrophages (Mphi1) differentiated in the presence of GM-CSF and infected with live Salmonella produce IL-23, IL-1beta and IL-18, but not IL-12. Supernatants of Salmonella-infected Mphi1 contained more IL-18 and IL-1beta as compared with supernatants of Mphi1 stimulated with isolated TLR agonists, and induced IFN-gamma production in human CD56(+) cells in an IL-23 and IL-1beta-dependent but IL-12-independent manner. In addition, IL-23 together with IL-18 or IL-1beta led to the production of GM-CSF in CD56(+) cells. Both IFN-gamma and GM-CSF enhanced IL-23 production by monocytes in response to TLR agonists, as well as induced IL-12 production.


CONCLUSIONS
The findings implicate a positive feedback loop in which IL-23 can enhance its release via induction of IFN-gamma and GM-CSF. The IL-23 induced cytokines allow for the subsequent production of IL-12 and amplify the IFN-gamma production in the type-1 cytokine pathway.
van de Wetering
Diederik
D
Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
de Paus
Roelof A
RA
van Dissel
Jaap T
JT
van de Vosse
Esther
E
D019002:CD56 Antigen / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D020382:Interleukin-18 / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis; D053759:Interleukin-23 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000382:microbiology*; D050296:Microbial Viability / Q000187:drug effects; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000382:microbiology*; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000276:immunology*; D012475:Salmonella / Q000187:drug effects / Q000276:immunology*; D012480:Salmonella Infections / Q000276:immunology; D013347:Subcellular Fractions / Q000187:drug effects / Q000382:microbiology; D051193:Toll-Like Receptors / Q000819:agonists
D019002:CD56 Antigen; D016207:Cytokines; D020382:Interleukin-18; D053583:Interleukin-1beta; D053759:Interleukin-23; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors; D018664:Interleukin-12; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor