IL-1β-Mediated Innate Immunity Is Amplified in the db/db Mouse Model of Type 2 Diabetes
Open accessAbstract
Chronic inflammation appears to play a critical role in type 2 diabetes and its complications. Here we tested the hypothesis that this inflammatory dysregulation affects the IL-1β system and has functional consequences in the brain. Diabetic, db/db, and nondiabetic, db/+, mice were administered i.p. LPS, a potent cytokine inducer, at a dose of 100 μg/kg/mouse. db/db mouse innate immune-associated sickness behavior was 14.8, 33, 44.7, and 34% greater than that of db/+ mice at 2, 4, 8, and 12 h, respectively. When a fixed dose of LPS was used (5 μg/mouse), db/db mouse sickness was again enhanced 18.4, 22.2, and 14.5% at 4, 8, and 12 h as compared with db/+ mice. In diabetic mice, peritoneal macrophages produced more IL-1β in response to LPS, and peritoneal levels of IL-1β induced by LPS were increased. Importantly, IL-1R antagonist and type 2 IL-1 receptor (IL-1R2) failed to up-regulate in response to LPS in db/db mice. Finally, both peripheral and central administration of IL-1β, itself, induced sickness in db/db mice that mimicked the effects of peripheral LPS and was significantly greater than that seen in db/+ mice. Taken together, these results indicate that IL-1β-mediated innate immunity is augmented in db/db mice both at the periphery and in the brain, and the mechanism is due to diabetes-associated loss of IL-1β counterregulation.
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This exacerbation can be seen in murine models of prion disease, type 2 diabetes and normal ageing, and might be due to priming.
“This phenomenon can be seen in murine models of prion disease96,97, type 2 diabetes39,98 and normal ageing98, and might be due to an effect called ‘priming’.”
From From inflammation to sickness and depression: when the immune system subjugates the brain (2008) · cites this paper as [39]
The Results section, “Intensity of the innate immune response to LPS is increased in type 2 diabetic mice” (page unavailable), reports an amplified response in db/db mice compared with nondiabetic controls. This supports the type 2 diabetes example attributed to this source. The cited paper does not establish the normal-ageing example or identify priming as the cause; the prion-disease example is attached to other citations. (LLM, conf=0.86)
Experimental — accuracy not yet measuredConditions of chronic inflammation exacerbate the sickness and depression-like behaviours that develop in response to acute peripheral inflammation.
“Conditions of chronic inflammation exacerbate the sickness and depression-like behaviours that develop in response to acute peripheral inflammation.”
From From inflammation to sickness and depression: when the immune system subjugates the brain (2008) · cites this paper as [39]
The Discussion reports that db/db mice, a model of type 2 diabetes associated with chronic low-grade inflammation, recovered more slowly from sickness behavior after a fixed dose of LPS than nondiabetic mice, although peak sickness behavior was similar. The study does not report a depression-like behavior outcome, and its findings do not establish the claim for conditions of chronic inflammation generally. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn obese mice, LPS induces more IL-1β but less IL-1 receptor antagonist and IL-1 receptor II than in non-obese mice.
“In obese mice, LPS induces more IL-1β but less IL-1 receptor antagonist and IL-1 receptor II (REF. 39) than in non-obese mice.”
From From inflammation to sickness and depression: when the immune system subjugates the brain (2008) · cites this paper as [39]
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References 51 · Cited by 86
Research works printed but not linked: 1
- Hirsch, E., V. M. Irikura, S. M. Paul, and D. Hirsh. 1996. Functions of interleukin 1 receptor antagonist in gene knockout and overproducing mice. Proc. Natl. Acad. Sci. USA 93:11008.
- Authors
- O’Connor, J. C., Satpathy, A., Hartman, M. E., Horvath, E. M., Kelley, K. W., Dantzer, R., Johnson, R. W., & Freund, G. G.
- Affiliations
- University of Illinois Urbana-Champaign (US)
- Centre National de la Recherche Scientifique (FR)
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-04
- Volume
- 174
- Issue
- 8
- Pages
- 4991-4997
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2171355986
- Cited by
- 86
- References
- 51
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 2 · 2020: 3 · 2018: 2 · 2017: 2 · 2016: 7 · 2015: 6 · 2014: 2 · 2013: 5 · 2012: 7
- FWCI
- 6.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (MH071349, R01MH071349)
- National Institute of Diabetes and Digestive and Kidney Diseases (DDK064862)
- National Institute of Neurological Disorders and Stroke (F30NS046227, NS046227)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- IL-1β, type 2 diabetes, db/db mice, innate immunity, sickness behavior, lipopolysaccharide, peritoneal macrophages, interleukin-1 receptor antagonist, IL1R2, neuroinflammation, chronic inflammation, counterregulation
- MeSH terms
- Animals, Base Sequence, Brain, Diabetes Mellitus, Type 2, DNA, Immunity, Innate, Interleukin-1, Lipopolysaccharides, Mice, Inbred C57BL, Mice, Mutant Strains, Recombinant Proteins, RNA, Messenger, Sialoglycoproteins, Receptors, Interleukin-1, Macrophages, Peritoneal, Models, Immunological, Mice, Receptors, Interleukin-1 Type II, Interleukin 1 Receptor Antagonist Protein
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