Research Letters

Haplotype associated with low interleukin-10 production in patients with severe asthma

Endogenous inhibitory mechanisms promote resolution of inflammation, enhance tissue repair and integrity, and promote homeostasis in the lung. These mechanisms include steroid hormones, regulatory T cells, IL-10, prostaglandin E₂, prostaglandin I₂, lipoxins, resolvins, protectins, maresins, glucagon-like peptide-1 receptor, adrenomedullin, nitric oxide, and carbon monoxide. Here we review the most recent literature regarding these endogenous inhibitory mechanisms in asthma, which remain a promising target for the prevention and treatment of asthma.

Interleukin-10 is an immunomodulatory cytokine that regulates important aspects of innate and cell-mediated immunity. This cytokine is synthesized by hematopoietic and non-hematopoietic cells, including macrophages and epithelial cells within the lung. The biologically active form of IL-10 is a homodimer that binds to the IL-10 receptor, which is expressed on leukocytes as well as structural cells. The primary function of IL-10 is to downregulate inflammation via inhibition of cytokine production and other inflammatory mediators. IL-10 is secreted in response to acute inflammation and under conditions that promote tolerance or anergy. The absence of IL-10 has been implicated in the pathogenesis of uncontrolled inflammation during the development of acute respiratory distress syndrome, chronic Pseudomonas colonization in cystic fibrosis, and allergic airways disease. However, IL-10 also possesses immunostimulatory properties for cytotoxic T cells and natural killer cells. Furthermore, IL-10 has been implicated as a mediator of critical illness-induced immunosuppression and matrix deposition/remodeling in interstitial lung disease. Thus, IL-10 is clearly a complex molecule with potential therapeutic uses in modulating inflammation, but its salutary anti-inflammatory effects must be weighed against its potentially stimulatory effects on cytotoxic activity and adverse impacts on host defense and fibrosis.

Although originally defined as a type 2 (T2) immune-mediated condition, non-T2 cytokines, such as IFN-γ and IL-17A, have been implicated in asthma pathogenesis, particularly in patients with severe disease. IL-10 regulates T_H cell phenotypes and can dampen T2 immunity to allergens, but its functions in controlling non-T2 cytokine responses in asthmatic patients are unclear.

We sought to determine how IL-10 regulates the balance of T_H cell responses to inhaled allergen.

Allergic airway disease was induced in wild-type, IL-10 reporter, and conditional IL-10 or IL-10 receptor α (IL-10Rα) knockout mice by means of repeated intranasal administration of house dust mite (HDM). IL-10 and IFN-γ signaling were disrupted by using blocking antibodies.

Repeated HDM inhalation induced a mixed IL-13/IL-17A response and accumulation of IL-10–producing forkhead box P3–negative effector CD4⁺ T cells in the lungs. Ablation of T cell–derived IL-10 increased the IFN-γ and IL-17A response to HDM, reducing IL-13 levels and airway eosinophilia without affecting IgE levels or airway hyperresponsiveness. The increased IFN-γ response could be recapitulated by IL-10Rα deletion in CD11c⁺ myeloid cells or local IL-10Rα blockade. Disruption of the T cell–myeloid IL-10 axis resulted in increased pulmonary monocyte–derived dendritic cell numbers and increased IFN-γ–dependent expression of CXCR3 ligands by airway macrophages, which is suggestive of a feedforward loop of T_H1 cell recruitment. Augmented IFN-γ responses in the HDM allergic airway disease model were accompanied by increased disruption of airway epithelium, which was reversed by therapeutic blockade of IFN-γ.

IL-10 from effector T cells signals to CD11c⁺ myeloid cells to suppress an atypical and pathogenic IFN-γ response to inhaled HDM.

Interleukin-10 (IL-10) is an anti-inflammatory cytokine associated with the inhibition of HIV replication. IL-10 polymorphisms were found to be linked to drug-induced hepatotoxicity. Hence we examined the prevalence of IL-10 (-819C/T,-1082A/G) polymorphisms in a total of 165 HIV patients which included 34 patients with hepatotoxicity, 131 without hepatotoxicity and 155 healthy controls by the PCR-RFLP method. In HIV patients with hepatotoxicity, the IL-10-819TT genotype increased the risk of ARV associated hepatotoxicity severity (OR = 1.61, P = 0.35). IL-10-819TT genotype was overrepresented in patients with hepatotoxicity as compared to healthy controls (26.5% vs. 13.5%, OR = 1.61, P = 0.46). IL-10 -819CT genotype was associated with advance HIV disease stage (OR = 0.49, P = 0.045). In HIV patients without hepatotoxicity, the IL-10-819TT genotype was more prevalent in patients consuming tobacco as compared to non-users (OR = 1.60, P = 0.41). In HIV patients without hepatotoxicity using both alcohol + efavirenz along with IL-10 -819CT genotype resulted in increased risk for the acquisition of ARV associated hepatotoxicity (OR = 4.00, P = 0.36). In multivariate logistic regression, taking nevirapine was associated with the risk hepatotoxicity severity (OR = 0.23, P = 0.005). In conclusion, an insignificant association between IL-10 polymorphisms and susceptibility to ARV associated hepatotoxicity.

Current research on the microbiome of humans and other species is revealing a fundamental role for the interaction between the microbiota and the immune system in determining the health status of the host. In these studies, the cytokine interleukin-10 (IL-10) is emerging as an important player. We present here an overview of the developments in the field emphasizing how the microbiota composition and its interplay with immune cells affect the health of the host through changes in IL-10 production. In addition, we explore the function that IL-10-producing immune cells may have on the qualitative and quantitative changes in the microbiota and thus influence the balance between microbial commensalism and pathogenicity. In the last section of this review, we present a summary of the strategies that target IL-10 for therapeutic purposes using probiotics, purified proteins or biologicals.

Vitamin D deficiency (VDD) is highly prevalent worldwide. The classical role for vitamin D is to regulate calcium absorption form the gastrointestinal tract and influence bone health. Recently vitamin D receptors and vitamin D metabolic enzymes have been discovered in numerous sites systemically supporting diverse extra-skeletal roles of vitamin D, for example in asthmatic disease. Further, VDD and asthma share several common risk factors including high latitude, winter season, industrialization, poor diet, obesity, and dark skin pigmentation.

Vitamin D has been demonstrated to possess potent immunomodulatory effects, including effects on T cells and B cells as well as increasing production of antimicrobial peptides (e.g. cathelicidin). This immunomodulation may lead to asthma specific clinical benefits in terms of decreased bacterial/viral infections, altered airway smooth muscle-remodeling and –function as well as modulation of response to standard anti-asthma therapy (e.g. glucocorticoids and immunotherapy).

Thus, vitamin D and its deficiency have a number of biological effects that are potentially important in altering the course of disease pathogenesis and severity in asthma. The purpose of this first of a two-part review is to review potential mechanisms whereby altering vitamin D status may influence asthmatic disease.