Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0235394 (wasting)
 8,040 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Duchenne muscular dystrophy (DMD) is the most common, lethal, muscle-wasting disease of childhood. Previous investigations have shown that muscle macrophages may play an important role in promoting the pathology in the mdx mouse model of DMD. In the present study, we investigate the mechanism through which macrophages promote mdx dystrophy and assess whether the phenotype of the macrophages changes between the stage of peak muscle necrosis (4 weeks of age) and muscle regeneration (12 weeks). We find that 4-week-old mdx muscles contain a population of pro-inflammatory, classically activated M1 macrophages that lyse muscle in vitro by NO-mediated mechanisms. Genetic ablation of the iNOS gene in mdx mice also significantly reduces muscle membrane lysis in 4-week-old mdx mice in vivo. However, 4-week mdx muscles also contain a population of alternatively activated, M2a macrophages that express arginase. In vitro assays show that M2a macrophages reduce lysis of muscle cells by M1 macrophages through the competition of arginase in M2a cells with iNOS in M1 cells for their common, enzymatic substrate, arginine. During the transition from the acute peak of mdx pathology to the regenerative stage, expression of IL-4 and IL-10 increases, either of which can deactivate the M1 phenotype and promote activation of a CD163+, M2c phenotype that can increase tissue repair. Our findings further show that IL-10 stimulation of macrophages activates their ability to promote satellite cell proliferation. Deactivation of the M1 phenotype is also associated with a reduced expression of iNOS, IL-6, MCP-1 and IP-10. Thus, these results show that distinct subpopulations of macrophages can promote muscle injury or repair in muscular dystrophy, and that therapeutic interventions that affect the balance between M1 and M2 macrophage populations may influence the course of muscular dystrophy.
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PMID:Shifts in macrophage phenotypes and macrophage competition for arginine metabolism affect the severity of muscle pathology in muscular dystrophy. 1899 17

Failure of mice to produce IL-10 has no effect on the bacterial burden of Mycobacterium tuberculosis infection in the lungs over the first 4-5 months of the disease. We show here that after 185 days of the infection, IL-10 gene disrupted (IL-10 KO) mice showed evidence of bacterial regrowth, began to show signs of wasting, and were moribund. We assessed the status of the acquired immune response and compared the lung lymphocyte cell populations, as well as the expression of Th1 (IL-12 and IFNgamma) and immunosuppressive (TGFbeta) cytokines, between IL-10 KO and wild type mice. The results demonstrated that at 60 days of the infection in the absence of IL-10 there was an increased expression of Th1 type immunity and an overall lack of control of the inflammatory responses. After 185 days of the infection, in the absence of IL-10 there was excessive pulmonary inflammation and increased expression of inflammatory cytokine TNFalpha. These results imply therefore that IL-10 plays a central role in dampening of the Th1 response and protection against chronic lung inflammation in the M. tuberculosis infected lung, and the complete removal of this regulatory component eventually leads to disease progression.
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PMID:Lack of IL-10 alters inflammatory and immune responses during pulmonary Mycobacterium tuberculosis infection. 1921 3

We have previously shown a reduction in anaemia and wasting malnutrition in infants <3 years old in Pemba Island, Zanzibar, following repeated anthelminthic treatment for the endemic gastrointestinal (GI) nematodes Ascaris lumbricoides, hookworm and Trichuris trichiura. In view of the low intensity of worm infections in this age group, this was unexpected, and it was proposed that immune responses to the worms rather than their direct effects may play a significant role in morbidity in infants and that anthelminthic treatment may alleviate such effects. Therefore, the primary aims of this study were to characterise the immune response to initial/early GI nematode infections in infants and the effects of anthelminthic treatment on such immune responses. The frequency and levels of Th1/Th2 cytokines (IL-5, IL-13, IFN-gamma and IL-10) induced by the worms were evaluated in 666 infants aged 6-24 months using the Whole Blood Assay. Ascaris and hookworm antigens induced predominantly Th2 cytokine responses, and levels of IL-5 and IL-13 were significantly correlated. The frequencies and levels of responses were higher for both Ascaris positive and hookworm positive infants compared with worm negative individuals, but very few infants made Trichuris-specific cytokine responses. Infants treated every 3 months with mebendazole showed a significantly lower prevalence of infection compared with placebo-treated controls at one year following baseline. At follow-up, cytokine responses to Ascaris and hookworm antigens, which remained Th2 biased, were increased compared with baseline but were not significantly affected by treatment. However, blood eosinophil levels, which were elevated in worm-infected children, were significantly lower in treated children. Thus the effect of deworming in this age group on anaemia and wasting malnutrition, which were replicated in this study, could not be explained by modification of cytokine responses but may be related to eosinophil function.
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PMID:Early exposure of infants to GI nematodes induces Th2 dominant immune responses which are unaffected by periodic anthelminthic treatment. 1943 45

The objectives were to determine if blood IL-10 levels rise during the early stages of acute (wasting) pre-pubescent malnutrition in metabolically distinct murine models known to depress inflammatory immune competence and whether systemic IL-10 production is affected in these pathologies. Weanling C57BL/6J mice were assigned to dietary protocols that elicited wasting pathologies mimicking the human diseases of marasmus (restricted-intake group) or incipient kwashiorkor (low-protein group). An age-matched control group also was included. Serum IL-10 bioactivities were assessed in the early (day 3) and advanced (day 14) stages of weight loss, and net systemic IL-10 production was assessed at the same stages of pathology by in vivo cytokine capture. Blood IL-10 levels were elevated in both malnourished groups relative to controls at days 3 and 14 (range of P values: 0.03-0.0001). Further, despite a limited supply of energy and nitrogenous substrates, the systemic IL-10 production rate was at least sustained in the malnourished groups and, in fact, was elevated in the marasmic group (P=0.05) throughout the progression of weight loss. IL-10 emerges as an anti-inflammatory mediator positioned to participate in initiating and upholding the depressed immune competence that accompanies acute pre-pubescent deficits of protein and energy.
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PMID:Elevated blood interleukin-10 levels and undiminished systemic interleukin-10 production rate prevail throughout acute protein-energy malnutrition in the weanling mouse. 1954

Plasma transforming growth factor (TGF)-beta levels are high in the advanced stages of acute (wasting) pre-pubescent deficits of protein and energy. Consequently, this potently anti-inflammatory cytokine may help to sustain the depression of inflammatory immune competence in acute malnutrition. Our objective was to determine if plasma TGF-beta levels rise during the early stages of acute malnutrition and, secondarily, to confirm the elevation reported previously in advanced weight loss. In two experiments, male and female C57BL/6J mice, initially 19 d old, consumed ad libitum a complete purified diet (group C), or in restricted daily quantities (group R) or had free access to an isoenergetic low-protein diet (group LP). TGF-beta bioactivity in platelet-poor plasma was determined via inhibition of Mv1Lu mink lung cell proliferation after 3 d (Expt 1, early stage) or 14 d (Expt 2, advanced stage) of dietary intervention. At 3 d, mean plasma TGF-beta bioactivities were 802 (C), 2952 (R) and 4678 (LP) pg/ml, and after 14 d mean bioactivities were 1786 (C), 5360 (R) and 5735 (LP) pg/ml. At both time points, the malnourished groups differed from age-matched controls (P </= 0.05). Thus, metabolically distinct weanling systems mimicking paediatric marasmus (group R) and kwashiorkor (group LP) exhibit an early rise in blood TGF-beta concentration, and this cytokine joins corticosterone and IL-10 as a third anti-inflammatory hormone temporally positioned to contribute to the initiation (and maintenance) of malnutrition-associated immune depression. This investigation contributes new insight into the active anti-inflammatory form of immune competence that appears to prevail in acute pre-pubescent malnutrition.
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PMID:The blood level of transforming growth factor-beta rises in the early stages of acute protein and energy deficit in the weanling mouse. 1994 77

Heart failure (HF) is associated with changes in the skeletal muscle (SM) which might be a consequence of the unbalanced local expression of pro- (TNF-alpha) and anti- (IL-10) inflammatory cytokines, leading to inflammation-induced myopathy, and SM wasting. This local effect of HF on SM may, on the other hand, contribute to systemic inflammation, as this tissue actively secretes cytokines. Since increasing evidence points out to an anti-inflammatory effect of exercise training, the goal of the present study was to investigate its effect in rats with HF after post-myocardial infarction (MI), with special regard to the expression of TNF-alpha and IL-10 in the soleus and extensor digitorum longus (EDL), muscles with different fiber composition. Wistar rats underwent left thoracotomy with ligation of the left coronary artery, and were randomly assigned to either a sedentary (Sham-operated and MI sedentary) or trained (Sham-operated and MI trained) group. Animals in the trained groups ran on a treadmill (0% grade at 13-20 m/min) for 60 min/day, 5 days/week, for 8-10 weeks. The training protocol was able to reverse the changes induced by MI, decreasing TNF-alpha protein (26%, P<0.05) and mRNA (58%, P<0.05) levels in the soleus, when compared with the sedentary MI group. Training also increased soleus IL-10 expression (2.6-fold, P<0.001) in post-MI HF rats. As a consequence, the IL-10/TNF-alpha ratio was increased. This "anti-inflammatory effect" was more pronounced in the soleus than in the EDL, suggesting a fiber composition dependent response.
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PMID:Exercise training changes IL-10/TNF-alpha ratio in the skeletal muscle of post-MI rats. 1994 15

Analysis of parasite-host interactions can reveal the intricacies of immunity and identify ways to modulate immunopathological reactions. We assessed the ability of a phosphate-buffered saline-soluble extract of adult Hymenolepis diminuta to suppress macrophage (human THP-1 cell line, murine peritoneal macrophages) activity in vitro and the impact of treating mice with this extract on colitis induced by dinitrobenzene sulfonic acid (DNBS). A high-molecular-mass fraction of adult H. diminuta (HdHMW) or excretory/secretory products reduced macrophage activation: lipopolysaccharide (LPS)-induced interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor alpha (TNF-alpha) and poly(I:C)-induced TNF-alpha and IL-6 were suppressed by HdHMW. The active component in the HdHMW extract was minimally sensitive to boiling and trypsin digestion, whereas the use of sodium metaperiodate, as a general deglycosylation strategy, indicated that the immunosuppressive effect of HdHMW was at least partially dependent on a glycan: treating the HdHMW with neuraminidase and alpha-mannosidase failed to inhibit its blockade of LPS-induced TNF-alpha production by THP-1 macrophages. Mice treated with DNBS developed colitis, as typified by wasting, shortening of the colon, macroscopic and microscopic tissue damage, and an inflammatory infiltrate. Mice cotreated with HdHMW (three intraperitoneal injections) displayed significantly less inflammatory disease, and this was accompanied by reduced TNF-alpha production and increased IL-10 and IL-4 production by mitogen-stimulated spleen cells. However, cotreatment of mice with neutralizing anti-IL-10 antibodies had only a minor impact on the anticolitic effect of the HdHMW. We speculate that purification of the immunosuppressive factor(s) from H. diminuta has the potential to lead to the development of novel immunomodulatory drugs to treat inflammatory disease.
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PMID:Extracts of the rat tapeworm, Hymenolepis diminuta, suppress macrophage activation in vitro and alleviate chemically induced colitis in mice. 2002 12

Th17 cells and Th1 cells coordinate to play a critical role in the formation of inflammatory bowel diseases. To examine how Th17 and Th1 cells are regulated at inflammatory sites, we used Th1-dominant CD4(+)CD45RB(high) T cell-transferred RAG-2(-/-) and Th1/Th17-mixed IL-10(-/-) mice. Interestingly, not only did colitic RAG-2(-/-) mice that were parabiosed with WT mice show significant amelioration of colitis, but amelioration of disease was also observed in those parabiosed with colitic IL-10(-/-) mice. To assess the interference between Th1 and Th17 colitogenic T cells, we co-transferred colitogenic CD4(+) T cells from the lamina propria (LP) of CD4(+)CD45RB(high) T cell-transferred RAG-2(-/-) mice and IL-10(-/-) mice into RAG-2(-/-) mice. Surprisingly, the co-transferred RAG-2(-/-) mice showed a vast cellular infiltration of LP CD4(+) T cells similar to that seen in RAG-2(-/-) mice re-transferred with the cells from colitic RAG-2(-/-) mice alone, but the co-transferred RAG-2(-/-) mice did not have the wasting symptoms, which are also absent in RAG-2(-/-) mice transferred with cells from colitic IL-10(-/-) mice alone. Furthermore, the percentages of Th1 and Th17 cells originating from IL-10(-/-) mice and those of Th1 cells originating from colitic RAG-2(-/-) mice were all significantly decreased in the co-transferred mice as compared with the singly-transferred paired RAG-2(-/-) mice, suggesting that Th1 and Th17 cells are in competition, and that their orchestration results in a merged clinical phenotype of the two types of murine colitis.
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PMID:Competition between colitogenic Th1 and Th17 cells contributes to the amelioration of colitis. 2070 84

The tolerance model of acute (i.e., wasting) pre-pubescent protein and energy deficits proposes that the immune depression characteristic of these pathologies reflects an intact anti-inflammatory form of immune competence that reduces the risk of autoimmune reactions to catabolically released self antigens. A cornerstone of this proposition is the finding that constitutive (first-tier) interleukin(IL)-10 production is sustained even into the advanced stages of acute malnutrition. The IL-10 response to inflammatory challenge constitutes a second tier of anti-inflammatory regulation and was the focus of this investigation. Weanling mice consumed a complete diet ad libitum, a low-protein diet ad libitum (mimicking incipient kwashiorkor), or the complete diet in restricted daily quantities (mimicking marasmus), and their second-tier IL-10 production was determined both in vitro and in vivo using lipopolysaccharide (LPS) and anti-CD3 as stimulants of innate and adaptive defences, respectively. Both early (3 days) and advanced (14 days) stages of wasting pathology were examined and three main outcomes emerged. First, classic in vitro systems are unreliable for discerning cytokine production in vivo. Secondly, in diverse forms of acute malnutrition declining challenge-induced IL-10 production may provide an early sign that anti-inflammatory control over immune competence is failing. Thirdly, and most fundamentally, the investigation provides new support for the tolerance model of malnutrition-associated inflammatory immune depression.
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PMID:Constitutive, but not challenge-induced, interleukin-10 production is robust in acute pre-pubescent protein and energy deficits: new support for the tolerance hypothesis of malnutrition-associated immune depression based on cytokine production in vivo. 2131 19

Scrapie is a prion-associated transmissible spongiform encephalopathy (TSE) of sheep and goats, and frequently serves as a comparative model for other prion diseases, such as chronic wasting disease and bovine spongiform encephalopathy. TSEs are unique neurologic disorders that do not appear to be accompanied by robust systemic immunologic responses. mRNA data suggest that cytokines are involved in scrapie progression. In this study, brain tissue, mesenteric lymph nodes, splenic tissue and serum from ovinized mice were screened for 62 cytokine and cytokine-related proteins at pre-clinical and clinical points of infection. Expression patterns were compared to brain histology and clinical presentation. Increased cytokine expression in the brain and periphery were noted in scrapie-positive animals before histologic changes or clinical signs were evident. Of the 62 proteins examined, only IL-10 and TIMP-1 were consistently expressed at increased levels in the serum throughout infection. These cytokines could suggest future targets for biomarkers of infection and may, as well, provide insight into the biologic dynamics of prion-associated neurologic diseases.
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PMID:Cytokine antibody array analysis in brain and periphery of scrapie-infected Tg338 mice. 2178 75


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