The role of the pro-inflammatory cytokine Interleukin-18, its processing enzyme Caspase-1, and potential alternative IL-18-activating pathways in atherosclerosis

Atherosclerosis is the predominant underlying pathology of cardiovascular disease, the most common cause of premature death in the industrialized world. Recent research attributed inflammation a crucial role in atherosclerosis. Indeed, atherosclerotic lesions are characterized by abundance of immune cells and their effector molecules, accelerating atherogenesis and eventually leading to clinical symptoms such as unstable angina, myocardial infarction, or stroke. We have recently implicated the pro-inflammatory cytokine interleukin (IL)-18 as a novel mediator in this disease. The present work aims to evaluate the in vivo role of this cytokine and its activating protease Caspase-1 in atherosclerosis. Interestingly, IL-18-deficiency limited early lesion development in hyperlipidemic mice but did not affect atherogenesis after prolonged hyperlipidemia. These studies suggest a direct role for IL-18 in disease progression extending beyond the classical function of this cytokine, the induction of interferon gamma. Additional experiments employing chimeric mice, that lacked the IL-18R alpha on either the hematopoietic or the vascular cells, generated by bone-marrow transplantation, revealed that IL-18R alpha does not participate in the pro-atherogenic effects of IL-18 Surprisingly, deficiency of Caspase-1 did not diminish atherogenesis, thus suggesting alternative mechanisms of IL-18 activation during atherosclerosis. Subsequent experiments tested whether matrix metalloproteinases (MMPs), enzymes prominently expressed in atherosclerotic lesions mediate the maturation of the IL-18 precursor (proIL-18). Indeed, several recombinant MMPs proteolytically cleaved the precursor in vitro, and MMP-2- and MMP-8 processed proIL-18 exhibited IL-18 activity. Sequence analysis of processed proIL-18 demonstrated that cleavage sites of MMP-2 and MMP-8 differ from that of Caspase-1. Finally, the presence of mature/processed IL-18 in atherosclerotic tissue of Caspase-1-deficient mice highlighted the potential in vivo relevance of such an alternative, MMP-mediated IL-18 activation mechanism for this pro-inflammatory disease. In sum, this work directly demonstrates the pro-atherogenic role of IL-18 independent of IL-18R alpha or Caspase-1. These surprising observations provide a novel understanding of IL-18 biology and may foster re-thinking of current approaches for the therapeutic intervention of this pathway in prevalent inflammatory diseases

ATVB Distinguished Scientist Award How Costimulatory and Coinhibitory Pathways Shape Atherosclerosis

Objective-Immune cells play a critical role in atherosclerosis. Costimulatory and coinhibitory molecules of the tumor necrosis factor receptor and CD28 immunoglobulin superfamilies not only shape T-cell and B-cell responses but also have a major effect on antigen-presenting cells and nonimmune cells. Approach and Results-Pharmacological inhibition or activation of costimulatory and coinhibitory molecules and genetic deletion demonstrated their involvement in atherosclerosis. This review highlights recent advances in understanding how costimulatory and coinhibitory pathways shape the immune response in atherosclerosis. Conclusions-Insights gained from costimulatory and coinhibitory molecule function in atherosclerosis may inform future therapeutic approaches

Circulating Levels of Interleukin-1 Family Cytokines in Overweight Adolescents

Objectives. Obesity and related diseases are dramatically increasing problems, particularly in children and adolescents. We determined circulating levels of different interleukin (IL)-1 family members in normal weight and overweight adolescents. Methods. Seventy male, Caucasian adolescents (13–17 years) were recruited. Thirty-five had a body-mass index (BMI) above the 90th age-specific percentile. IL-1α, IL-1β, IL-1 receptor antagonist (IL-1ra), and IL-18 were determined using multiplex-technology. Results. IL-18 concentrations were higher in the overweight group compared to normal weight (161.6 ± 40.7 pg/ml versus 134.7 ± 43.4 pg/ml, P = .009). Concentrations of circulating IL-1β levels were below the detection threshold. IL-18 (R2:0.355, P < .01) and IL-1ra (R2:0.287, P < .05) correlated with BMI, whereas IL-1α did not. Conclusions. Accumulating data indicate the importance of the endocrine function of adipose tissue for the pathophysiological consequences of obesity-related co-morbidities. Since IL-18 is involved in the pathogenesis of different cardiovascular diseases, we conclude that IL-18 may represent a link between obesity and related co-morbidities in children and adolescents

Elevated Plasma Levels of Interleukin-12p40 and Interleukin-16 in Overweight Adolescents

Introduction. Obesity during adolescence is an increasing problem for both the individual and health care systems alike. In Western world countries, childhood adiposity has reached epidemic proportions. It is known that elevated levels of proinflammatory cytokines can be found in the plasma of obese patients. In this study, we sought to determine the relation between IL-12p40, IL-12p70, and Interleukin-16 (IL-16) in overweight adolescents. Materials and Methods. Seventy-nine male Caucasian adolescents aged 13-17 years were included in this study. Thirty-seven of them had a body mass index (BMI) above the 90th age-specific percentile. Il-12p40, IL-12p70, and IL-16 were measured from plasma using Luminex multiplex technology. Results. Both IL-12p40 and IL- 16 concentrations were significantly increased in overweight subjects compared to normal weight controls (IL-12p40: 1086.6 pg/mL +/- 31.7 pg/mL SEM versus 1228.6 pg/mL +/- 43.5 pg/mL SEM;IL-16 494.0 pg/mL +/- 29.4 pg/mL SEM versus 686.6 pg/mL +/- 52.5 pg/mL SEM, P < 0.05 and P < 0.01, resp.). No differences were found for IL-12p70. Conclusions. Based on these results, we believe that the increased levels of IL-12p40 and IL-16 are associated with an ongoing inflammatory response in obese individuals and could lead to the development of disease conditions related to obesity

Depletion of CD40 on CD11c(+) cells worsens the metabolic syndrome and ameliorates hepatic inflammation during NASH

The co-stimulatory CD40-CD40L dyad plays a central role in fine-tuning immune reactions, including obesity-induced inflammation. Genetic ablation of CD40L reduced adipose tissue inflammation, while absence of CD40 resulted in aggravated metabolic dysfunction in mice. During obesity, CD40 expressing CD11c(+) dendritic cells (DC) and macrophages accumulate in adipose tissue and liver. We investigated the role of CD40(+)CD11c(+) cells in the metabolic syndrome and nonalcoholic steatohepatitis (NASH). DC-CD40-ko mice (CD40(fl/fl)CD11c(cre)) mice were subjected to obesity or NASH. Obesity and insulin resistance were induced by feeding mice a 54% high fat diet (HFD). NASH was induced by feeding mice a diet containing 40% fat, 20% fructose and 2% cholesterol. CD40(fl/fl)CD11c(cre )mice fed a HFD displayed increased weight gain, increased adipocyte size, and worsened insulin resistance. Moreover, CD40(fl/fl)CD11c(cre )mice had higher plasma and hepatic cholesterol levels and developed profound liver steatosis. Overall, regulatory T cell numbers were decreased in these mice. In NASH, absence of CD40 on CD11c(+) cells slightly decreased liver inflammation but did not affect liver lipid accumulation. Our experiments suggest that CD40 expressing CD11c(+) cells can act as a double-edged sword: CD40 expressing CD11c(+) cells contribute to liver inflammation during NASH but are protective against the metabolic syndrome via induction of regulatory T cells

Mycobacterium avium subsp. paratuberculosis Infection in a Patient with HIV, Germany

Mycobacterium avium subsp. paratuberculosis (MAP), the causative agent of Johne disease in ruminants, has been incriminated as the cause of Crohn disease in humans. We report the first case of human infection with MAP in a patient with HIV; infection was confirmed by obtaining isolates from several different specimen types

Elevated Plasma Levels of Interleukin-12p40 and Interleukin-16 in Overweight Adolescents

Introduction. Obesity during adolescence is an increasing problem for both the individual and health care systems alike. In Western world countries, childhood adiposity has reached epidemic proportions. It is known that elevated levels of proinflammatory cytokines can be found in the plasma of obese patients. In this study, we sought to determine the relation between IL-12p40, IL-12p70, and Interleukin-16 (IL-16) in overweight adolescents. Materials and Methods. Seventy-nine male Caucasian adolescents aged 13–17 years were included in this study. Thirty-seven of them had a body mass index (BMI) above the 90th age-specific percentile. Il-12p40, IL-12p70, and IL-16 were measured from plasma using Luminex multiplex technology. Results. Both IL-12p40 and IL-16 concentrations were significantly increased in overweight subjects compared to normal weight controls (IL-12p40: 1086.6 pg/mL ± 31.7 pg/mL SEM versus 1228.6 pg/mL ± 43.5 pg/mL SEM; IL-16 494.0 pg/mL ± 29.4 pg/mL SEM versus 686.6 pg/mL ± 52.5 pg/mL SEM, P<0.05 and P<0.01, resp.). No differences were found for IL-12p70. Conclusions. Based on these results, we believe that the increased levels of IL-12p40 and IL-16 are associated with an ongoing inflammatory response in obese individuals and could lead to the development of disease conditions related to obesity