Interleukin-10 regulation in normal and asthmatic subjects
ABSTRACT Interleukin-10 or cytokine synthesis inhibitory factor has important antiinflammatory activities in immune diseases. We speculated that diminished IL-10 production in asthma would permit the unopposed synthesis of proinflammatory cytokines, contributing to the development and severity of asthma. Our data demonstrate constitutive secretion of IL-10 into bronchoalveolar lavage (BAL) fluid of normal, nonasthmatic subjects (130 +/- 61 pg/ml; n = 8). Asthmatic patients' BAL fluid was characterized by diminished concentrations of IL-10 (9 +/- 18 pg/ml; n = 8; p < 0.01 compared with that of normal subjects). By using the RNA-based polymerase chain reaction, we demonstrated that diminished IL-10 occurred as a result of inhibition of transcription. IL-10 transcription, but not protein, was observed at the time of the late asthmatic response. We speculate that the subsequent appearance of IL-10 protein could contribute to the resolution of the late asthmatic response. Similar to what was observed in the BAL fluid, peripheral blood mononuclear cells of patients with asthma demonstrated decreased spontaneous (0.01 +/- 0.01 ng/ml-asthmatic and 0.09 +/- 0.04 ng/ml-normal; p < 0.05) and stimulated (0.60 +/- 0.22 ng/ml-asthmatic and 1.69 +/- 0.49 ng/ml-normal; p < 0.05) IL-10 production compared with normal subjects. In support of the hypothesis that IL-10 mitigates the development of inflammation, we demonstrated that the addition of a neutralizing anti-IL-10 antibody to resting peripheral blood mononuclear cell cultures of normal subjects stimulated the spontaneous production of interferon-gamma (10.4 +/- 4.3 to 152.4 +/- 23.6 ng/ml; p < 0.01). Finally, we reasoned that corticosteroids might exert at least part of their antiinflammatory activity through the induction of IL-10 secretion. However, methylprednisolone inhibited the lipopolysaccharide-stimulated production of IL-10 (2.34 +/- 0.49 ng/ml IL-10 with lipopolysaccharide alone to 1.11 +/- 0.38 ng/ml in the additional presence of 10(-6) mol/L methylprednisolone; p < 0.05).
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- "IL-10 is one of the major anti-inflammatory cytokines, with important roles in counterbalancing hyperactive immune responses to protect the body from excessive cell and organ damage. Moreover, IL-10 is critically involved in tolerance against potential allergens, and impairment in IL-10 signaling may result in autoimmune reactions like asthma.23 IL-10 can be produced by regulatory T cells but also monocytes and B cells.24 "
ABSTRACT: Interleukins represent a class of immunomodulatory cytokines, small intercellular signaling proteins, that are critically involved in the regulation of immune responses. They are produced in large amounts by various cell types during inflammatory reactions, and the balance of cytokines determines the outcome of an immune response. Therefore, cytokines are regarded as interesting therapeutic targets for the treatment of patients with liver diseases. Mouse models provide a good tool for in vivo studies on cytokine function, as human and mouse cytokines share many homologies. Sophisticated mouse models either mimicking distinct pathological conditions or targeting cytokines and cytokine-signaling pathways in the liver or even in distinct cellular compartments have provided enormous insight into the different functions of interleukins during hepatic inflammation. Interleukins may have pro- as well as anti-inflammatory functions in chronic liver diseases, some interleukins even both, dependent on the inflammatory stimulus, the producing and the responding cell type. IL-17, for example, promotes hepatic fibrogenesis through activation of hepatic stellate cells and facilitates development of liver cancer through recruitment of myeloid-derived suppressor cells. IL-22, on the other hand, protects from development of fibrosis or steatohepatitis. IL-12 balances T-helper (Th)-1 and Th2 cell responses in infectious disease models. IL-13 and IL-33, two cytokines related to Th2 cells and innate lymphoid cells, promote fibrotic responses in the liver. IL-10 is the prototypic anti-inflammatory interleukin with tissue-protective functions during chronic liver injury and fibrogenesis. Despite its critical role for inducing the acute-phase response in the liver, IL-6 signaling is protective during fibrosis progression, but promotes hepatocellular carcinoma. Experimental studies in mice help to define the exact influence of a specific cytokine on the outcome of chronic liver diseases and to identify useful therapeutic targets.Clinical and Experimental Gastroenterology 09/2014; 7:297-306. DOI:10.2147/CEG.S43737
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- "There may also be either a synergism or amplification of effects with the interaction of Th2 allergic inflammatory pathways in atopic asthmatics that is also associated with production of ROS in the airway, which may potentiate bronchospasm and bronchoconstriction associated with asthma (Cai et al. 2008; D'Amato et al. 2002; Lee and Yang 2012). In this context, it is interesting to consider that asthmatics have a deficiency of production of IL-10 in the airway (Borish et al. 1996), for reasons as yet unexplained, but which could be critical to the exaggerated effects of SO 2 seen in asthmatics, but not seen in nonasthmatics, who are IL-10 sufficient. A question that remains unsolved is whether asthmatics are extraordinarily sensitive to the effects of SO 2 because they cannot mount a significant anti-inflammatory response, with a deficiency in the production of IL-10. "
ABSTRACT: The driving environmental factors behind the development of the asthma phenotype remain incompletely studied and understood. Here, we present an overview of inhaled allergic/atopic and mainly nonallergic/nonatopic or toxicant shapers of the asthma phenotype, which are present in both the indoor and outdoor environment around us. The inhaled allergic/atopic factors include fungus, mold, animal dander, cockroach, dust mites, and pollen; these allergic triggers and shapers of the asthma phenotype are considered in the context of their ability to drive the immunologic IgE response and potentially induce interactions between the innate and adaptive immune responses, with special emphasis on the NADPH-dependent reactive oxygen-species-associated mechanism of pollen-associated allergy induction. The inhaled nonallergic/nonatopic, toxicant factors include gaseous and volatile agents, such as sulfur dioxide, ozone, acrolein, and butadiene, as well as particulate agents, such as rubber tire breakdown particles, and diesel exhaust particles. These toxicants are reviewed in terms of their relevant chemical characteristics and hazard potential, ability to induce airway dysfunction, and potential for driving the asthma phenotype. Special emphasis is placed on their interactive nature with other triggers and drivers, with regard to driving the asthma phenotype. Overall, both allergic and nonallergic environmental factors can interact to acutely exacerbate the asthma phenotype; some may also promote its development over prolonged periods of untreated exposure, or possibly indirectly through effects on the genome. Further therapeutic considerations should be given to these environmental factors when determining the best course of personalized medicine for individuals with asthma.Advances in Experimental Medicine and Biology 01/2014; 795:43-73. DOI:10.1007/978-1-4614-8603-9_4 · 1.96 Impact Factor
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- "Studies of the effects of corticosteroid treatment on IL-10 are mixed. IL-10 expression is greater during budesonide treatment compared with placebo  and serum IL-10 increases after triamcinolone  while inhibition of IL-10 by corticosteroid treatment can also occur . "
ABSTRACT: While most of the clinical benefits of inhaled corticosteroid (ICS) therapy may occur at low doses, results of dose-ranging studies are inconsistent. Although symptom/lung function response to low and high dose ICS medication is comparable, it is uncertain whether low dose ICSs are as effective as high dose in the treatment of inflammation and remodeling. 22 mild or moderate asthmatic adult subjects (corticosteroid free for > 2 months) participated in a randomized, parallel group study to compare effects of fluticasone propionate (FP) 200 mcg/day and 1000 mcg/day. Alveolar macrophage (AM)-derived cytokines and basement membrane thickness (BMT) were measured at baseline and after 7 weeks treatment while symptoms, spirometry, exhaled nitric oxide (eNO) and airway hyperresponsiveness (AHR) to mannitol at baseline and 6 weeks. FP improved spirometry, eNO, symptoms and AHR with no difference between low and high dose FP. Both high and low dose FP reduced GM-CSF, TNF-alpha and IL-1ra, with no change in BMT and with no differences between low and high dose FP. 200 μg/day of FP was as effective as 1000 μg/day in improving asthma control, airway inflammation, lung function and AHR in adults in the short term. Future studies should examine potential differential effects between low and high dose combination therapy (ICS/long acting beta agonist) on inflammation and airway remodeling over longer treatment periods.Respiratory research 02/2012; 13(1):11. DOI:10.1186/1465-9921-13-11 · 3.09 Impact Factor