Anti-inflammatory Effect Of Interleukin-10 Research Articles

Platelet shipped IL-10 enhances drug delivery for attenuating I/R- or UUO-induced renal injury

Inflammatory factors have emerged as key pathophysiological molecules involved in the progression of acute and chronic kidney disease. However, the anti-inflammatory effect of interleukin-10 (IL-10) is largely attenuated because of its insufficient concentration in an injured kidney. To overcome this challenge, we demonstrate in this study that platelet (PLT) camouflaged IL-10 (IL-10@PLT) can selectively accumulate in injured kidneys for treating kidney inflammation and resulting complications. In this system, the PLT drug carrier maintained its original attributes over the study duration, with a good inflammation target effect, confirmed by in vivo imaging. IL-10@PLT could be activated and aggregated, and also released IL-10 at the injury site in the kidney because of high levels of Tumor Necrosis Factor-α (TNF-α). Compared with free IL-10, IL-10@PLT displayed a higher anti-inflammatory effect with fewer mitochondrial disorders (P < 0.01) and lower expression of NOD-like receptor (NLR)-P3 (NLRP3) (P < 0.05), resulting in reduced inflammation and pyroptosis in ischemia/reperfusion injury (I/R) mice. Treatment with IL-10@PLT also exhibited significantly reduced nuclear factor kappa-B (NF-kB) expression, reduced inflammatory response, as well as improved renal fibrosis (P < 0.05) in the recovery phase in unilateral ureteral obstruction (UUO) mice. At the same time, IL-10@PLT therapy continued to exhibit a favorable safety profile. This study established a promising approach for I/R- and UUO-induced kidney injury and fibrosis by taking advantage of the high accumulation and strong anti-inflammatory of IL-10@PLT. Our study also reveals the importance PLT as an effective drug carrier for targeted therapies.

AB0074 Alkylating Agents Enhance Interleukin-10 Secretion from B Cells via P38 MAP Kinase Activation

BackgroundAlkylating agents such as melphalan and bendamustine are commonly used in the treatments of tumors, especially hematologic malignancies. However, the exact mechanisms of their actions to B cells have not...

Protective and detrimental roles of IL-10 in HIV pathogenesis.

Successful pathogen clearance depends on a finely orchestrated equilibrium between inflammatory immune responses and immunoregulatory mechanisms that limit collateral tissue damage. The cytokine interleukin 10 (IL-10) has been shown to play a critical role in this balance in numerous infectious diseases. Studies in animal models have revealed that IL-10 gene-knockout or signaling blockade can enhance resistance to pathogens, and substantially facilitate viral clearance. These same interventions in other infections however, result in more severe disease due to the inability of the immune system to adequately contain the pathogen load, and to control immune-mediate damage. This IL-10-regulated balance is also apparent in human infectious diseases. This review summarizes evidence that IL-10 impacts many aspects of HIV pathogenesis, including the regulation of HIV-specific CD4 and CD8 T cell functions, as well as modulation of HIV-replication in PBMC subsets. Genetic polymorphisms in the IL-10 gene promoter that lead to decreased IL-10 expression have been associated with more rapid disease progression in late stages of HIV infection, suggesting that the anti-inflammatory effects of IL-10 may be protective in the setting of chronic immune activation. We conclude with a discussion of important questions remaining, and the potential for therapeutic intervention based on manipulation of the IL-10 pathway.

Suppression of glomerulosclerosis by adenovirus-mediated IL-10 expression in the kidney.

Glomerulosclerosis is a common morphologic result seen in almost all progressed renal diseases, and is the characteristic change in focal segmental glomerulosclerosis (FSGS). The most convincing hypothesis for glomerulosclerosis is cytokine-mediated injury by infiltrating immune cells in the glomerulus and tubulointerstitial area. This study investigated whether the anti-inflammatory effect of interleukin-10 (IL-10) when expressed by a recombinant adenoviral vector can prevent the onset of glomerulosclerosis in FGS/Kist mice (an animal model with naturally occurring renal failure initiated by FSGS). Each group of mice received recombinant adenoviruses encoding human IL-10 (Ad:hIL-10) by intraparenchymal injection at 6 weeks and were examined for cytokine expression, glomerular sclerotic index, and proteinuria. After injection of Ad:hIL-10 to the kidney, IL-10 expression was found to last over 20 days. Mice treated with Ad:hIL-10 were shown to have a significant reduction in the glomerular sclerotic index at 10 weeks when compared to control groups. The level of proteinuria in Ad:hIL-10-treated mice was also significantly reduced. About 50% of the urine samples of naive and Ad:LacZ-treated groups had severe levels of proteinuria. By contrast, at 10 weeks the group treated with Ad:hIL-10 had lower levels of proteinuria and transforming growth factor-beta1 (TGF-beta1) expression. These results demonstrate that IL-10 effectively prevents the development of glomerulosclerosis in FGS/Kist mice, and IL-10 gene therapy may be of use for the treatment of renal failure.

Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice.

The mechanisms underlying the action of the potent anti-inflammatory interleukin-10 (IL-10) are poorly understood. Here we show that, in murine macrophages, IL-10 induces expression of heme oxygenase-1 (HO-1), a stress-inducible protein with potential anti-inflammatory effect, via a p38 mitogen-activated protein kinase-dependent pathway. Inhibition of HO-1 protein synthesis or activity significantly reversed the inhibitory effect of IL-10 on production of tumor necrosis factor-alpha induced by lipopolysaccharide (LPS). Additional experiments revealed the involvement of carbon monoxide, one of the products of HO-1-mediated heme degradation, in the anti-inflammatory effect of IL-10 in vitro. Induction of HO-1 by IL-10 was also evident in vivo. IL-10-mediated protection against LPS-induced septic shock in mice was significantly attenuated by cotreatment with the HO inhibitor, zinc protoporphyrin. The identification of HO-1 as a downstream effector of IL-10 provides new possibilities for improved therapeutic approaches for treating inflammatory diseases.

Therapeutic implications of interleukin-10 in surgical disease.

Pharmacological therapy of surgical disease often involves manipulating the physiologic balance between pro- and anti-inflammatory responses. Many agents target only one aspect of the inflammatory cascade. Originally identified as a protein elaborated by T-lymphocytes, IL-10 appears to globally inhibit cytokine production. The purpose of this manuscript is to examine the immunomodulatory and anti-inflammatory effects of interleukin-10 (IL-10) in an attempt to define the clinical utility of IL-10, both as a marker of and as a therapeutic strategy for intervention in inflammatory and immune-mediated diseases. IL-10 is elaborated from multiple sources and has diverse cellular effects to regulate immune and inflammatory responses. Accumulating evidence suggests that the anti-inflammatory influence of IL-10 observed at the cellular level may be manipulated to impact the immune and inflammatory-mediated responses associated with injury and sepsis, gastrointestinal and cardiovascular disease, and transplantation. In conclusion, IL-10 is an important mediator of immune and anti-inflammatory responses in surgical disease and, as such, has therapeutic promise as an immunomodulator and as an anti-inflammatory agent.

Anti-Inflammatory Effect of Interleukin-10 in Rabbit Immune Complex-Induced Colitis

Background: Interleukin-10 (IL-10) is an anti-inflammatory cytokine that downregulates the secretion of pro-inflammatory cytokines and additionally induces the secretion of anti-inflammatory cytokines, thus possibly leading to reduction of chronic inflammation in inflammatory bowel disease. In this study we evaluated the anti-inflammatory effect of IL-10 in a model of acute colitis in rabbits. Methods

Pulmonary lymphoid cell activation and cytokine expression in murine AIDS-associated interstitial pneumonitis.

Limited information is available about the pathogenesis of acquired immune deficiency syndrome (AIDS)-associated idiopathic interstitial pneumonitis, a common noninfectious complication of human immunodeficiency virus (HIV) infection. Infection of C57B1/6 mice with LP-BM5 retrovirus, a murine model of AIDS, leads to development of a diffuse interstitial pneumonitis that displays many features of human AIDS-associated interstitial pneumonitis. To further characterize the cellular and molecular features of this lung disease, the temporal development of cellular infiltration, cytokine expression, and virus replication were evaluated in lung tissue of virus-infected mice. Persistent expression of viral RNA was detectable in lungs as early as 1 wk after infection. Infiltration of the lungs by CD4+ and CD8+ T cells, by IgG+ and IgA+ B cells, and by macrophages was observed by 4 wk after infection and continued through 8 wk of infection. Histologically, cellular infiltration was most pronounced in peribronchial and perivascular regions, whereas inflammation of alveolar septae and alveolar spaces was minimal. In contrast to normals, T cells from infected lungs were immunodeficient in that they failed to proliferate in response to the mitogen concanavalin A (ConA). However, evaluation of cytokine mRNA expression by interstitial lung lymphoid cells indicated that cells from infected lungs were chronically activated, in that elevated expression of interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) was observed throughout the course of infection. Similarly, expression by interstitial lung lymphoid cells of mRNA for the proinflammatory cytokine IL-1 and the fibrogenic cytokine transforming growth factor-beta (TGF-beta) was also increased following infection. These results indicate that retrovirus-induced immunodeficiency in mice is associated with infiltration and chronic activation of lymphoid cells in the lungs. Furthermore, simultaneous expression of IL-10, IFN-gamma, and TGF-beta suggests that cytokine-expressing cells in infected lungs may be unresponsive to inhibitory and antiinflammatory effects of IL-10 and/or TGF-beta, thus contributing to chronicity of inflammation in this disorder.

Interleukin-10

Interleukin-10 (IL-10) is a potent anti-inflammatory and immunosuppressive cytokine secreted by several cell types. Most anti-inflammatory effects of IL-10 are caused by its ability to deactivate macrophages and monocytes, whereas its immunosuppressive properties are due to functional inhibition of both antigen-presenting cells and T cells. On the other hand, IL-10 also exerts immunostimulatory effects, especially on B cells, CD8+ cytotoxic T cells and natural killer cells. In vivo administration of recombinant IL-10 (rIL-10) efficiently prevents experimental septic shock induced by endotoxin, staphylococcal superantigen or cecal ligation and puncture, as well as experimental autoimmune diseases mediated by T helper type 1 (T(H)1) cells and other inflammatory disorders. rIL-10 exerts paradoxical effects in cancer models, where it promotes tumour rejection, probably due to its stimulatory properties on cytotoxic cells. On the other hand, rIL-10 increases the severity of experimental infections caused by fungi or bacteria, and enhances systemic autoimmune features in mice with spontaneous lupus syndrome. Although the therapeutic potential of rIL-10 in human diseases seems promising, the multiple facets of rIL-10 in experimental immunopathology indicate that the success of clinical trials with rIL-10 will depend both on the appropriate selection of the patient populations to be treated and on the early detection of possible adverse effects.

The anti-inflammatory effect of interleukin-10 in a rabbit model of colitis

The anti-inflammatory effect of interleukin-10 in a rabbit model of colitis

Human Kupffer cells secrete IL-10 in response to lipopolysaccharide (LPS) challenge

Background/Aims: Kupffer cells are involved in local immunoregulation in the liver by secretion of cytokines and direct cellular contact. They are able to influence the function of other liver cells, i.e. sinusoidal endothelial cells, Ito cells and hepatocytes. The three known major functions of Kupffer cells are clearance of endotoxin from the portal circulation, release of soluble mediators and presentation of antigen. Methods: Human Kupffer cells were isolated by collagenase perfusion followed by centrifugal elutriation and analyzed for cytokine secretion after 3 days in culture. Results: We found that freshly isolated human Kupffer cells secreted the anti-inflammatory cytokine interleukin-10 in response to stimulation with lipopolysaccharide. The release of interleukin-10 was maximal 12–24 h after lipopolysaccharide challenge. Furthermore, we could show that exogenous interleukin-10 downregulated the release of the proinflammatory cytokines interleukin-6 and tumor necrosis factor α by Kupffer cells after lipopolysaccharide stimulation. The release of interleukin-6 was maximal 24 h after stimulation and interleukin-10 inhibited interleukin-6 release after 6 h. Tumor necrosis factor α showed maximal secretion 6 h after stimulation and exogenous interleukin-10 also downregulated the tumor necrosis factor α release after 6 h. Conclusions: Kupffer cells are exposed physiologically to lipopolysaccharide present in portal venous blood. Given the known anti-inflammatory effect of interleukin-10, our findings of secretion of interleukin-10 by Kupffer cells in response to lipopolysaccharide and suppression of interleukin-6 and tumor necrosis factor α release by Kupffer cells in vitro through exogenous interleukin-10 suggest an important role for interleukin-10 in the regulation of the local immune response in the liver sinusoid.