IL-12 and IFN-γ in host defense against mycobacteria and salmonella in mice and men

doi:10.1016/S0952-7915(99)80055-7

Current Opinion in Immunology

Volume 11, Issue 3, June 1999, Pages 346-351

https://doi.org/10.1016/S0952-7915(99)80055-7 Get rights and content

The development of gene-knockout mice and the identification of gene-deficient humans have improved our understanding of the role of IL-12 and IFN-γ in host defense. Comparison of experimental and natural infections has shown that animals and humans genetically deficient in immunity mediated by IL-12 or IFN-γ are highly susceptible to mycobacteria and salmonella. Impaired secretion of, or response to, IFN-γ is the common pathogenic mechanism that accounts for impaired granuloma formation and uncontrolled growth of bacteria within macrophages. The axis formed between IL-12 and IFN-γ is essential for protective immunity against mycobacteria and salmonella in mice and men.

References and recommended reading (10)

TrinchieriG
Interleukin-12: a cytokine at the interface of inflammation and immunity
Adv Immunol
(1998)
MagramJ et al.
IL-12-deficient mice are defective in IFNγ production and type 1 cytokine responses
Immunity
(1996)
BachE et al.
The interferon gamma receptor: a paradigm for cytokine receptor signaling
Annu Rev Immunol
(1997)
DaltonDK et al.
Multiple defects of immune cell function in mice with disrupted interferon-γgenes
Science
(1993)
HuangS et al.
Immune response in mice that lack the interferon-γ receptor
Science
(1993)

There are more references available in the full text version of this article.

Cited by (300)

Interleukin-12 induces IFN-γ secretion and STAT signaling implying its potential regulation of Th1 cell response in Nile tilapia
2023, Fish and Shellfish Immunology
As a pleiotropic cytokine consisting of IL-12p35 and IL-12p40, Interleukin-12 (IL-12) features in inflammation regulation and anti-bacterial immunity. While IL-12 homologs have been identified in non-mammalian species, the precise mechanisms by which IL-12 contributes to early adaptive immune responses in vertebrates remain incompletely understood. Herein, an evolutionary conserved Oreochromis niloticus IL-12 (defined as OnIL-12) was identified by synteny characterization, structural comparisons and phylogenetic pattern of IL-12p35b and IL-12p40a. IL-12p35b and IL-12p40a exhibited widespread expression in lymphoid-related tissues of tilapia, while their mRNA expression in head-kidney demonstrated a significant increase after Edwardsiella piscicida infection. Compared with other lymphocytes, recombinant OnIL-12 (rOnIL-12) displayed stronger affinity binding to T cells. Although stimulation of lymphocytes with the p35b or p40a subunit resulted in a significant induction of IFN-γ expression, rOnIL-12 showed stronger potential to promote IFN-γ expression than these subunits. rOnIL-12 not only elevated the mRNA expression level Th1 cell-associated transcription factor T-bet in lymphocytes, but also increased the proportion of CD4-1⁺IFN-γ⁺ lymphocytes. Moreover, the mRNA and phosphorylation levels of STAT1, STAT3, STAT4 and STAT5 were enhanced by rOnIL-12. These findings will offer previous evidence for further exploration into the regulatory mechanisms of Th1 cellular immunity in early vertebrates.
Effects of melittin on laying performance and intestinal barrier function of quails
2023, Poultry Science
To study the effects of melittin on egg-laying performance and intestinal barrier of quails, 240 quails (aged 70 d) were randomly divided into 4 groups with 6 replicates (10 quails per replicate). They were fed with basal diet (group B), basal diet + 0.08 g/kg melittin (group BA1), basal diet + 0.12 g/kg melittin (group BA2) and basal diet + 0.16 g/kg melittin (group BA3). The experiment lasted for 21 days. The eggs were collected every day. At the end of the experiment, duodenal, jejunal, and ileal tissues were collected, and the cecal contents were sampled. Intestinal antioxidant index, barrier function, and intestinal flora were analyzed. The results showed that the addition of melittin significantly increased the laying rate and average egg weight. Addition of melittin significantly increased the antioxidant function, mechanical barrier, immune barrier, and the villus height to crypt depth ratio of small intestine. Addition of melittin had no significant effect on the α and β diversity of cecal flora, but significantly increased the abundance of Bacteroidales at family level and genus level. Bioinformatics analysis of cecal content showed significant increase in COG functional category of cytoskeleton, and significant decrease in RNA processing and modification in group BA2. KEGG functional analysis showed significant decrease in steroid biosynthesis, caffeine metabolism, and cytochrome P450 pathways in group BA2. In conclusion, addition of 0.12 g/kg melittin to feed improved the laying performance and the intestinal antioxidant capacity and barrier function of quails but had no significant effect on the composition and structure of cecal microbial community. This study provides experimental data and theoretical basis for the application of melittin as a new quail feed additive.
Cholesterol metabolism: from lipidomics to immunology
2022, Journal of Lipid Research
Citation Excerpt :
BCG is known to activate TLR4 and stimulate IFNγ production (97, 98), which will lead to macrophage biosynthesis of 25-HC in normal macrophages; however, an absence of CH25H enzyme will prevent this, resulting perhaps in overactivation of inflammasomes. Significantly, genetic deficiency in IFNγ or its receptor IFNGR (IFNγ receptor) enhances host susceptibility to M. tuberculosis (79, 99). This may be explained by a failure of macrophages to produce 25-HC and hence remove paracrine protection of epithelial cells from M. tuberculosis spread.
Oxysterols, the oxidized forms of cholesterol or of its precursors, are formed in the first steps of cholesterol metabolism. Oxysterols have interested chemists, biologists, and physicians for many decades, but their exact biological relevance in vivo, other than as intermediates in bile acid biosynthesis, has long been debated. However, in the first quarter of this century, a role for side-chain oxysterols and their C-7 oxidized metabolites has been convincingly established in the immune system. 25-Hydroxycholesterol has been shown to be synthesized by macrophages in response to the activation of Toll-like receptors and to offer protection against microbial pathogens, whereas 7α,25-dihydroxycholesterol has been shown to act as a chemoattractant to lymphocytes expressing the G protein-coupled receptor Epstein-Barr virus-induced gene 2 and to be important in coordinating the action of B cells, T cells, and dendritic cells in secondary lymphoid tissue. There is a growing body of evidence that not only these two oxysterols but also many of their isomers are of importance to the proper function of the immune system. Here, we review recent findings related to the roles of oxysterols in immunology.
Iron in immune cell function and host defense
2021, Seminars in Cell and Developmental Biology
The control over iron availability is crucial under homeostatic conditions and even more in the case of an infection. This results from diverse properties of iron: first, iron is an important trace element for the host as well as for the pathogen for various cellular and metabolic processes, second, free iron catalyzes Fenton reaction and is therefore producing reactive oxygen species as a part of the host defense machinery, third, iron exhibits important effects on immune cell function and differentiation and fourth almost every immune activation in turn impacts on iron metabolism and spatio-temporal iron distribution. The central importance of iron in the host and microbe interplay and thus for the course of infections led to diverse strategies to restrict iron for invading pathogens. In this review, we focus on how iron restriction to the pathogen is a powerful innate immune defense mechanism of the host called “nutritional immunity”. Important proteins in the iron-host-pathogen interplay will be discussed as well as the influence of iron on the efficacy of innate and adaptive immunity. Recently described processes like ferritinophagy and ferroptosis are further covered in respect to their impact on inflammation and infection control and how they impact on our understanding of the interaction of host and pathogen.
Effects of Salmonella enterica serovar typhimurium sseK1 on macrophage inflammation-related cytokines and glycolysis
2021, Cytokine
Salmonella enterica serovar Typhimurium (S. Typhimurium), an important virulent intracellular pathogen, causes inflammatory gastroenteritis or typhoid. Macrophages play a key role in innate immunity against Salmonella. Salmonella secreted effector K1 (SseK1) encoded by SPI2 has been identified a novel translocated protein. To investigate the role of Salmonella enterica serovar Typhimurium sseK1 about the inflammation and glycolysis in macrophages, the levels of IL-1β, IL-2, IL-4, IL-6, IFN-γ and Nitric Oxide in macrophages infected by S. Typhimurium SL1344 wild-type (WT) group, ΔsseK1 mutant group and sseK1-complemented group were measured. And the glycolysis level was determined in RAW 264.7 cells infected with these different Salmonella strains. The results showed that groups infected by wild-type strain, sseK1 mutant and sseK1-complemented strain upregulated the production of IL-1β, IL-2, IL-4, IL-6, IFN-γ and NO at 3 h, 6 h and 12 h, respectively. The production of IL-1β, IL-2, IL-4, IL-6, IFN-γ and NO in wild-type strain group were significantly decreased compared with the ΔsseK1 mutant group, which suggested that sseK1 down-regulated the production of related inflammatory factors. Moreover, hexokinase, lactic acid and pyruvic acid levels significantly decreased by infection with sseK1 mutant compared to the wild-type strain. The ATP level of ΔsseK1 mutant group was remarkably increased than WT group and sseK1-complemented group. These indicated that the sseK1 enhanced the level of glycolysis of macrophages infected by S. Typhimurium. In summary, the results demonstrated that sseK1 can down-regulate the inflammation-related cytokines and enhance the glycolysis level in macrophages infected by S. Typhimurium, which may be beneficial for S. typhimurium survival in macrophages.
Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria
2020, Cell
Citation Excerpt :
Key observations made in T-bet-deficient mice were validated in this human patient with T-bet deficiency: (1) the development of TH1 cells and their production of effector cytokines, including IFN-γ in particular, requires T-bet (Szabo et al., 2000, 2002); (2) the development of NK and iNKT cells is dependent on T-bet (Townsend et al., 2004); and (3) the regulation of T-bet-dependent targets, including CXCR3, TNF, and IFNG, involves both direct transactivation and epigenetic modulation (Miller and Weinmann, 2010). Accordingly, T-bet-deficient mice are highly vulnerable to mycobacteria, including M. tuberculosis and M. avium (Matsuyama et al., 2014; Sullivan et al., 2005), like mice deficient for other genes that govern IFN-γ immunity (Jouanguy et al., 1999). By contrast, despite the requirement of T-bet for immunity to a broad spectrum of pathogens following experimental inoculation in mice (Bakshi et al., 2006; Harms Pritchard et al., 2015; Hultgren et al., 2004; Kao et al., 2011; Lebrun et al., 2015; Oakley et al., 2013; Ravindran et al., 2005; Rosas et al., 2006; Svensson et al., 2005; Szabo et al., 2002), the only apparent infectious phenotype of the T-bet-deficient patient is MSMD.
Inborn errors of human interferon gamma (IFN-γ) immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to inherited deficiency of the transcription factor T-bet. The patient has extremely low counts of circulating Mycobacterium-reactive natural killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2⁺ γδ T lymphocytes, and of Mycobacterium-non reactive classic T_H1 lymphocytes, with the residual populations of these cells also producing abnormally small amounts of IFN-γ. Other lymphocyte subsets develop normally but produce low levels of IFN-γ, with the exception of CD8⁺ αβ T and non-classic CD4⁺ αβ T_H1^∗ lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2⁺ γδ T cells) and IFN-γ production by them, with mycobacterium-specific, IFN-γ-producing, purely adaptive CD8⁺ αβ T, and CD4⁺ αβ T_H1^∗ cells unable to compensate for this deficit.

View all citing articles on Scopus

View full text

IL-12 and IFN-γ in host defense against mycobacteria and salmonella in mice and men

Adv Immunol

Immunity

The interferon gamma receptor: a paradigm for cytokine receptor signaling

Annu Rev Immunol

Multiple defects of immune cell function in mice with disrupted interferon-γgenes

Science

Immune response in mice that lack the interferon-γ receptor

Science