N-3 fatty acids modulate Th1 and Th2 dichotomy in diabetic pregnancy and macrosomia
Introduction
Through different experimental models of diabetes, it has been well established that the secretion of cytokines plays an important role in the regulation of tolerance of islet antigens [1]. These cytokines are produced during the islet inflammatory response and their production, in part, may explain the ability of CD4+ Th cells alone to cause β-cell destruction [1]. On the basis of production of cytokines, Th cells can be classified into two principal populations, Th1 and Th2. Th1 cells support cell-mediated immunity and as a consequence promote inflammation, cytotoxicity and delayed type hypersensitivity, whereas Th2 cells support humoral immunity and downregulate the inflammatory actions of Th1 cells [2]. Th1 cells secrete IL-2, IFN-γ and TNF-β, while Th2 cells secrete IL-4, IL-5, IL-6, IL-10 and IL-13 [3].
In the non-obese diabetic (NOD) mouse, the most common animal model of human type I diabetes, insulin-dependent diabetes mellitus (IDDM) results from autoimmune destruction of pancreatic β-cells, mediated by both CD4+ and CD8+T-cells [1]. It has been reported that the pathogenic activity of β-cell autoreactive CD4+T-cells in these mice can be inhibited if the predominant pattern of cytokines is shifted from Th1 (primarily IFN-γ) to Th2 (primarily IL-4) profile [2]. It is interesting to mention that the hyporesponsiveness of Th2 cells may also favor the development of a Th1 cell-mediated environment in the pancreas, leading to loss of immunological tolerance to β-cell autoantigens and onset of diabetes in NOD mice and humans [4]. In human beings suffering from type I diabetes mellitus, a low secretion of IL-4 from mitogen-stimulated T cells has been reported [5]. The general conclusion is drawn that Th1 cytokines play a pathogenic role, while Th2 cytokines assure regulatory function, and thus mediate protection during diabetes [1], [2], [6], [7], [8].
Epidemiological, clinical and experimental studies have suggested that maternal type I diabetes during pregnancy is an important risk factor for fetal overnutrition and macrosomia, and for the development of an increased susceptibility to obesity and diabetes in their offspring [9], [10]. The abnormalities in humoral and cell-mediated immunity in type I diabetic females may persist during pregnancy and, hence may complicate immune-foetal interaction [11]. As far as T-cell activation during pregnancy in type I diabetic mothers and their macrosomic offspring is concerned, only a few studies are available on the subject [11]. In fact, fully activated T-cells are detected in the cord blood of infants and mothers with type I diabetes but not in infants from normal mothers [11]. Moreover, from birth up to 15 years of age, the percentage of total T-cells was higher in children of type I diabetic mothers than in those of healthy mothers [12]. An increase in MHC class II positive lymphocytes has been observed in infants of type I diabetic mothers compared to controls [13]. Moreover, the newborns of type I diabetic mothers showed a significant reduction in natural killer (NK) lymphocytes, indicating a deficit in natural immunity at birth [14]. Newborns of type I diabetic mothers showed an increase in the number of CD4+T-cells [15]. Furthermore, production of IL-1 and IL-2 in the culture supernatants of mitogen-stimulated lymphocytes of these newborns was higher than that in controls [16]. However, the role of pancreatic and splenic Th subsets in the modulation of these pathologies has not yet been explored.
It has been recently well established that n-3 polyunsaturated fatty acids (PUFA) exert immunosuppressive effects [17] and, consequently, these agents have been used in the management of a number of inflammatory and autoimmune diseases, including rheumatoid arthritis and multiple sclerosis [18]. Generally, n-3 PUFA suppress mitogen-stimulated proliferation of lymphocytes isolated from lymph nodes [17]. Hence, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the most potent immunomodulators of the n-3 PUFA family [19]. It has been shown that dietary EPA and DHA are equipotent in inhibiting IL-2 production in mice [19] and rats [20]. The production of IFN-γ is also decreased by these fatty acids [21]. The n-3 PUFA have also been used in the management of diabetes mellitus in human beings [22] and experimental models [17].
The above observations demonstrate that type I diabetes mellitus is a Th1-biased disease and n-3 polyunsaturated fatty acids (PUFA) exert immunomodulatory effects. In the present study, we propose a hypothesis that the Th1 and Th2 dichotomy may be involved in diabetes mellitus during pregnancy and macrosomia, and that a diet rich in n-3 PUFA may modulate Th1 and Th2 balance during these pathologies.
Section snippets
Chemicals
EPAX-7010 was generously provided by Polaris, Quimper (France). SYBR® Green supermix was procured from Bio-Rad, Marnes-la-Coquette (France). Vegetable oil (Isio-4) was purchased from Lesieur, Neuilly-sur-Seine (France). All other chemical products were obtained from In-vitrogen Life Technologies, Groningen (The Netherlands).
Animals, diets and experimental design
Adult Wistar rats were obtained from Ifa-Credo (Lyon, France). After mating, the first day of gestation was estimated by the presence of spermatozoids in vaginal smears.
Expression of mRNA of Th1 and Th2 cytokines in the pancreas and spleen of rats with DP
Fig. 1 shows that the expression of mRNA of Th1 cytokines (IL-2 and IFN-γ) and IL-4 was downregulated in the pancreas and spleen of animals with DP in comparison with control rats. However, the expression of IL-10 mRNA was either upregulated in the pancreas or remained unchanged in the spleen of rats with DP as compared to control animals (Fig. 1).
The expression of mRNA of IL-2 and IFN-γ in the pancreas and spleen of rats with DP was not significantly different between the standard diet and the
Discussion
The administration of five low doses of STZ to mice [6], [30] and rats [23] represents a good model of diabetes development, and this is for several reasons: 1) islet lesions in this experimental model resemble to those of human insulitis, with a predominance of CD8+T-cells [30]; 2) the animals used are normal and do not have an underlying immune abnormalities like BB rat, being lymphopenic with few peripheral CD8+T-cells [31], and NOD mice which have systemic immune abnormalities [32]; 3) the
Acknowledgements
We gratefully acknowledge the Office of Scholarship Programme of IDB that granted a scholarship to one of the authors (A. Yessoufou). This work was supported by a financial support from the Burgundy Region, Dijon (France).
References (66)
- et al.
Transcriptional regulation of Th1/Th2 polarization
Immunol Today
(2000) - et al.
Th1 and Th2 CD4 + T cells in the pathogenesis of organ-specific autoimmune diseases
Immunol Today
(1995) - et al.
Insulin dependent diabetes mellitus in the non-obese diabetic mouse: a disease mediated by T cell energy?
Life Sci
(1994) - et al.
Multidose streptozotocin induction of diabetes in BALB/cBy mice induces a T cell proliferation defect in thymocytes which is reversible by interleukin-4
Cell Immunol
(1999) - et al.
Differential regulation of Th1-type and Th2-type cytokine profiles in pancreatic islets of C57BL/6 and BALB/c mice by multiple low doses of streptozotocin
Immunobiology
(2002) Immunobiology of normal and diabetic pregnancy
Immunol Today
(1990)- et al.
Dietary n-3 fats as adjunctive therapy in a prototypic inflammatory disease: issues and obstacles for use in rheumatoid arthritis
Prostaglandins Leukot Essent Fatty Acids
(2003) - et al.
Dietary (n-3) polyunsaturated fatty acids suppress murine lymphoproliferation, interleukin-2 secretion, and the formation of diacylglycerol and ceramide
J Nutr
(1997) - et al.
Long-chain polyunsaturated fatty acids and chemically induced diabetes mellitus. Effect of omega-3 fatty acids
Nutrition
(2003) - et al.
Immunostimulation circumvents diabetes in NOD/Lt mice
J Autoimmun
(1989)
Animal models of diabetes
Am J Med
Intra-uterine transmission of disease
Placenta
Shifts in the TH1/TH2 balance during human pregnancy correlate with apoptotic changes
Biochem Biophys Res Commun
Recombinant human IL-10 prevents the onset of diabetes in the non-obese diabetic mouse
Clin Immunol Immunopathol
Inhibition of diabetes in NOD mice by human pregnancy factor
Hum Immunol
Implications of dietary fatty acids during pregnancy on placental, foetal and postnatal development – a Review
Placenta
Liver triacylglycerols and free fatty acids in streptozotocin-induced diabetic rats have atypical n-6 and n-3 pattern
Com Biochem Physiol Part C
Dietary (n-3) polyunsaturated fatty acids modulate murine Th1/Th2 balance toward the Th2 pole by suppression of Th1 development
J Nutr
Regulation of calcium signalling by docosahexaenoic acid in human T-cells. Implication of CRAC channels
J Lipid Res
Eicosapentaenoic acid and docosahexaenoic acid modulate MAP kinase (ERK1/ERK2) signaling in human T cells
J Lipid Res
Diacylglycerols containing Omega 3 and Omega 6 fatty acids bind to RasGRP and modulate MAP kinase activation
J Biol Chem
Prevention of autoimmune insulitis by delivery of a chimeric plasmid encoding interleukin-4 and interleukin-10
J Control Release
Immunoregulatory and cytokine imbalances in the pathogenesis of IDDM. Therapeutic intervention by immunostimulation?
Diabetes
Decreased IL-4 production in new onset type I insulin-dependent diabetes mellitus
J Immunol
Th1 to Th2 cytokine shifts in non-obese diabetic mice: sometimes an outcome, rather than the cause, of diabetes resistance elicited by immunostimulation
J Immunol
Implication of lipids in macrosomia of diabetic pregnancy: can n-3 polyunsaturated fatty acids exert beneficial effects?
Clin Sci
Risk of complications of pregnancy in women with type 1 diabetes: nationwide prospective study in the Netherlands
Br Med J
Alterations of lymphocytes subsets in children of diabetic mothers
Diabetologia
Immunology in diabetic pregnancy: activated T-cells in diabetic mothers and neonates
Diabetologia
Analysis of T-lymphocytte subsets after phyhemagglutinin stimulation in normal and type 1 diabetic mothers and their infants
Am J Reprod Immunol
Lymphocyte populations and responses to mitogens in infants of diabetic mothers
J Clin Labo Immunol
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