Upregulation of Proinflammatory Cytokine Production in Response to Bacterial Pathogen-Associated Molecular Patterns in Dogs with Diabetes Mellitus Undergoing Insulin Therapy
Free accessMeeting reportFirst published online May, 2012
Upregulation of Proinflammatory Cytokine Production in Response to Bacterial Pathogen-Associated Molecular Patterns in Dogs with Diabetes Mellitus Undergoing Insulin Therapy
Metabolic alterations associated with diabetes mellitus alter innate immunity. Dogs often develop infectious or inflammatory complications related to diabetes mellitus, yet little is known about the effects of diabetes mellitus on the immune system in this species.
Methods:
Prospective evaluation in dogs with poorly regulated spontaneous type 1 diabetes mellitus (T1DM). In vitro leukocyte cytokine response to lipopolysaccharide (LPS), lipoteichoic acid (LTA), and peptidoglycan (PG) was compared between dogs with T1DM and healthy dogs. Additionally, the effect of acute in vitro glucose exposure on leukocyte tumor necrosis factor (TNF) production from healthy dogs was measured.
Results:
Leukocytes from dogs with T1DM had significantly greater TNF production after LTA and PG stimulation compared with leukocytes from healthy dogs. Leukocyte interleukin (IL)-6 production was greater after stimulation with LPS, LTA, PG, and phosphate-buffered saline in the T1DM group. No such difference was noted when evaluating IL-10 production between groups regardless of stimulant. Dogs with T1DM had significantly greater IL-6 to IL-10 production ratios than healthy dogs. Acute exposure to dextrose did not augment cytokine production from healthy canine leukocytes.
Conclusions:
Dogs with T1DM have altered innate immunity characterized by upregulation of proinflammatory cytokine production without a concurrent change in anti-inflammatory cytokine production. This may be one explanation for the common infectious and inflammatory complications associated with T1DM in dogs.
CatchpoleBRisticJMFleemanLMDavisonLJ. Canine diabetes mellitus: Can old dogs teach us new tricks?Diabetologia.2005;48 (10): 1948–56.
2.
CatchpoleBKennedyLJDavisonLJOllierWE. Canine diabetes mellitus: From phenotype to genotype. J Small Anim Pract.2008;49 (1): 4–10.
3.
NambamBAggarwalSJainA. Latent autoimmune diabetes in adults: A distinct but heterogeneous clinical entity. World J Diabetes.2010;1 (4): 111–5.
4.
DavisonLJWeeninkSMChristieMRHerrtageMECatchpoleB. Autoantibodies to GAD65 and IA-2 in canine diabetes mellitus. Vet Immunol Immunopathol.2008;126 (1–2): 83–90.
5.
GuptillLGlickmanLGlickmanN. Time trends and risk factors for diabetes mellitus in dogs: Analysis of veterinary medical data base records (1970–1999). Vet J.2003;165 (3): 240–7.
6.
RucinskyRCookAHaleySNelsonRZoranDLPoundstoneM; American Animal Hospital Association. AAHA diabetes management guidelines. J Am Anim Hosp Assoc.2010;46 (3): 215–24.
7.
FeldmanECNelsonRW. Canine and feline endocrinology and reproduction. 3rd ed.St. Louis: Elsevier; 2004.
8.
ArayaAVPavezVPerezCGonzalezFColumboAAguirreASchiattinoIAguillonJC. Ex vivo lipopolysaccharide (LPS)-induced TNF-alpha, IL-1beta, IL-6 and PGE2 secretion in whole blood from type 1 diabetes mellitus patients with or without aggressive periodontitis. Eur Cytokine Netw.2003;14 (3): 128–33.
9.
WuHPChenCHHsiehHCLiuYC. Effects of insulin and glucose on cytokine production from peripheral blood mononuclear cells. Chang Gung Med J.2008;31 (3): 253–9.
10.
TurinaMFryDEPolkHCJr.Acute hyperglycemia and the innate immune system: Clinical, cellular, and molecular aspects. Crit Care Med.2005;33 (7): 1624–33.
11.
SchuetzPCastroPShapiroNI. Diabetes and sepsis: Preclinical findings and clinical relevance. Diabetes Care.2011;34 (3): 771–8.
12.
PeikesHMorrisDOHessRS. Dermatologic disorders in dogs with diabetes mellitus: 45 cases (1986–2000). J Am Vet Med Assoc.2001;219 (2): 203–8.
13.
HumeDZDrobatzKJHessRS. Outcome of dogs with diabetic ketoacidosis: 127 dogs (1993–2003). J Vet Intern Med.2006;20 (3): 547–55.
14.
JinYLinD. Fungal urinary tract infections in the dog and cat: A retrospective study (2001–2004). J Am Anim Hosp Assoc.2005;41 (6): 373–81.
15.
HessRSSaundersHMVan WinkleTJWardCR. Concurrent disorders in dogs with diabetes mellitus: 221 cases (1993–1998). J Am Vet Med Assoc.2000;217 (8): 1166–73.
16.
DiehlKJ. Long-term complications of diabetes mellitus, part II: Gastrointestinal and infectious. Vet Clin North Am Small Anim Pract.1995;25 (3): 731–51.
17.
NemzekJAAgrodniaMDHauptmanJG. Breed-specific pro-inflammatory cytokine production as a predisposing factor for susceptibility to sepsis in the dog. J Vet Emerg Crit Care.2007;17 (4): 368–72.
18.
DeitschelSJKerlMEChangCHDeClueAE. Age-associated changes to pathogen-associated molecular pattern-induced inflammatory mediator production in dogs. J Vet Emerg Crit Care (San Antonio).2010;20 (5): 494–502.
19.
DeClueAEJohnsonPJDayJLAmorimJRHonakerAR. Pathogen associated molecular pattern motifs from Gram-positive and Gram-negative bacteria induce different inflammatory mediator profiles in equine blood. Vet J.2011. Epub ahead of print.
20.
FowlerBLAxiakSMDeClueAE. Blunted pathogen-associated molecular pattern motif induced TNF, IL-6 and IL-10 production from whole blood in dogs with lymphoma. Vet Immunol Immunopathol.2011;144 (1–2): 167–71.
21.
ReuschCELiehsMRHoyerMVochezerR. Fructosamine. A new parameter for diagnosis and metabolic control in diabetic dogs and cats. J Vet Intern Med.1993;7 (3): 177–82.
22.
DeClueAECohnLALechnerESBryanMEDodamJR. Effects of subanesthetic doses of ketamine on hemodynamic and immunologic variables in dogs with experimentally induced endotoxemia. Am J Vet Res.2008;69 (2): 228–32.
23.
LoisaPRinneTLaineSHurmeMKaukinenS. Anti-inflammatory cytokine response and the development of multiple organ failure in severe sepsis. Acta Anaesthesiol Scand.2003;47 (3): 319–25.
24.
FossNTFoss-FreitasMCFerreiraMACardiliRNBarbosaCMFossMC. Impaired cytokine production by peripheral blood mononuclear cells in type 1 diabetic patients. Diabetes Metab.2007;33 (6): 439–43.
25.
Foss-FreitasMCFossNTRassiDMDonadiEAFossMC. Evaluation of cytokine production from peripheral blood mononuclear cells of type 1 diabetic patients. Ann N Y Acad Sci.2008;1150: 290–6.
26.
GeerlingsSEBrouwerECVan KesselKCGaastraWStolkRPHoepelmanAI. Cytokine secretion is impaired in women with diabetes mellitus. Eur J Clin Invest.2000;30 (11): 995–1001.
27.
Foss-FreitasMCFossNTDonadiEAFossMC. In vitro TNF-alpha and IL-6 production by adherent peripheral blood mononuclear cells obtained from type 1 and type 2 diabetic patients evaluated according to the metabolic control. Ann N Y Acad Sci.2006;1079: 177–80.
28.
WehrweinGNeumeierMSchafflerAKoppAWeigertJAbkeSScholmerichJBuechlerC. Lipopolysaccharide regulated protein expression is only partly impaired in monocytes from patients with type I diabetes. Cardiovasc Diabetol.2006;5: 5.
29.
HatanakaEMonteagudoPTMarrocosMSCampaA. Neutrophils and monocytes as potentially important sources of proinflammatory cytokines in diabetes. Clin Exp Immunol.2006;146 (3): 443–7.
30.
KulsengBSkjåk-BraekGFøllingIEspevikT. TNF production from peripheral blood mononuclear cells in diabetic patients after stimulation with alginate and lipopolysaccharide. Scand J Immunol.1996;43 (3): 335–40.
31.
ShahBRHuxJE. Quantifying the risk of infectious diseases for people with diabetes. Diabetes Care.2003;26 (2): 510–3.
32.
MullerLMGorterKJHakEGoudzwaardWLSchellevisFGHoepelmanAIRuttenGE. Increased risk of common infections in patients with type 1 and type 2 diabetes mellitus. Clin Infect Dis.2005;41 (3): 281–8.
33.
HâncuNNeteaMGBaciuI. High glucose concentrations increase the tumor necrosis factor-alpha production capacity by human peripheral blood mononuclear cells. Rom J Physiol.1998;35 (3–4): 325–30.
34.
ShapiroLDinarelloCA. Hyperosmotic stress as a stimulant for proinflammatory cytokine production. Exp Cell Res.1997;231 (2): 354–62.
35.
OttoNMSchindlerRLunABoenischOFreiUOppertM. Hyperosmotic stress enhances cytokine production and decreases phagocytosis in vitro. Crit Care.2008;12 (4): R107.
36.
SpatzMEiblNHinkSWolfHMFischerGFMayrWRSchernthanerGEiblMM. Impaired primary immune response in type-1 diabetes. Functional impairment at the level of APCs and T-cells. Cell Immunol.2003;221 (1): 15–26.
37.
BenbarekHDeby-DupontGCaudronIGrulkeSDebyCLamyMSerteynD. Interactions between lipopolysaccharides and blood factors on the stimulation of equine polymorphonuclear neutrophils. Vet Immunol Immunopathol.1998;64 (4): 313–22.
