Leptin regulates proinflammatory immune responses

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Abstract

<p class="first" id="d9220435e115">Obesity is associated with an increased incidence of infection, diabetes, and cardiovascular disease, which together account for most obesity-related morbidity and mortality. Decreased expression of leptin or of functional leptin receptors results in hyperphagia, decreased energy expenditure, and obesity. It is unclear, however, whether defective leptin-dependent signal transduction directly promotes any of the conditions that frequently complicate obesity. Abnormalities in tumor necrosis factor alpha expression have been noted in each of the above comorbid conditions, so leptin deficiency could promote these complications if leptin had immunoregulatory activity. Studies of rodents with genetic abnormalities in leptin or leptin receptors revealed obesity-related deficits in macrophage phagocytosis and the expression of proinflammatory cytokines both in vivo and in vitro. Exogenous leptin up-regulated both phagocytosis and the production of proinflammatory cytokines. These results identify an important and novel function for leptin: up-regulation of inflammatory immune responses, which may provide a common pathogenetic mechanism that contributes to several of the major complications of obesity. </p>

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Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity.

G Trinchieri (1995)

Interleukin-12 (IL-12) is a heterodimeric cytokine produced mostly by phagocytic cells in response to bacteria, bacterial products, and intracellular parasites, and to some degree by B lymphocytes. IL-12 induces cytokine production, primarily of IFN-gamma, from NK and T cells, acts as a growth factor for activated NK and T cells, enhances the cytotoxic activity of NK cells, and favors cytotoxic T lymphocyte generation. In vivo IL-12 acts primarily at three stages during the innate resistance/adaptive immune response to infection: 1. Early in the infection, IL-12 is produced and induces production from NK and T cells of IFN-gamma, which contributes to phagocytic cell activation and inflammation; 2. IL-12 and IL-12-induced IFN-gamma favor Th1 cell differentiation by priming CD4+ T cells for high IFN-gamma production; and 3. IL-12 contributes to optimal IFN-gamma production and to proliferation of differentiated Th1 cells in response to antigen. The early preference expressed in the immune response depends on the balance between IL-12, which favors Th1 responses, and IL-4, which favors Th2 responses. Thus, IL-12 represents a functional bridge between the early nonspecific innate resistance and the subsequent antigen-specific adaptive immunity.

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Impaired immunity in obesity: suppressed but reversible lymphocyte responsiveness.

S. Tanaka, S. Inoue, F Isoda … (1993)

Although obese people have been reported to have a higher incidence of infections and some types of cancer, the immunocompetence of obese subjects remains poorly understood. To investigate whether obesity affects immunity, we studied obese subjects (BMI > 30 kg/m2) whose health was uncomplicated by any other disorder, including hyperglycemia. We compared mitogen-induced blastogenic response of peripheral blood lymphocytes in 34 obese subjects (mean +/- s.e. BMI: 38.4 +/- 2.0 kg/m2) and 35 non-obese controls (BMI: 21.3 +/- 0.4 kg/m2) who were matched for age and sex. The effects of weight reduction were also evaluated in 19 obese persons (BMI: 36.4 +/- 1.8 kg/m2) on a very low calorie diet. Mean (+/- s.e.) intracellular incorporation of [3H]-thymidine, on stimulation of T lymphocytes with either phytohaemagglutinin (PHA) or concanavalin A (Con A), and B lymphocytes with pokeweed mitogen, was significantly diminished in obese subjects compared to non-obese controls (47552 +/- 6917 vs. 83720 +/- 6252 cpm, P < 0.001; 30301 +/- 6018 vs. 45942 +/- 3723 cpm, P < 0.05; 13669 +/- 2971 vs. 23735 +/- 2048 cpm, P < 0.01, respectively). After weight reduction (BMI: 27.8 +/- 1.2 kg/m2), the mean T lymphocyte responses to PHA and Con A were increased significantly vs. baseline (98404 +/- 2444 vs. 50337 +/- 9516 cpm, P < 0.05 and 69523 +/- 15480 vs. 36695 +/- 8006 cpm, P < 0.05, respectively). Depressed blastogenesis of B lymphocytes was also augmented but was not statistically significant. The results suggest that obese subjects have underlying immune impairment in responsiveness of lymphocytes and that these impairments are reversible with adequate weight reduction.