Periodontitis is associated to increased systemic inflammation in postmyocardial infarction patients.

OBJECTIVE: Periodontitis has been independently associated to cardiovascular disease. However, the biological mechanisms underlying such association are still partially unknown. Thus, this study aimed to discover immunological clues accounting for the increased risk of myocardial infarction (MI) in patients having periodontitis. METHODS: We included 100 patients with a first MI, 50 with and 50 without severe periodontitis, and 100 age-matched, sex-matched and area-matched controls from the Periodontitis and Its Relation to Coronary Artery Disease Study. Participants underwent comprehensive clinical and laboratory examinations 6-10 weeks after the MI and plasma expression of 92 inflammation-related markers was assessed through proximity extension assay. RESULTS: Patients who had an MI displayed altered expression of CCL19, TNFRSF9 and LAP TGF-ß1 in comparison with controls. TNFRSF9 correlated significantly with the amount of alveolar bone loss. MI patients with deep periodontal pockets showed increased white cell count and higher expression of FGF-21, HGF, OSM, CCL20 and IL-18R1 than patients without. White cell count correlated significantly with four of these proteins. CONCLUSIONS: Collectively, our results indicate molecular markers that could be responsible for the increased systemic inflammatory activity in patients with MI with periodontitis.

Increased interleukin 18 activity in adolescents with early-onset psychosis is associated with cortisol and depressive symptoms.

OBJECTIVE: Evidence indicates that the pathophysiology of adult psychosis involves immune dysregulation, but its associations with stress are often not considered. The inflammatory cytokine interleukin (IL)-18, which is elevated in adult schizophrenia, is suggested to be sensitive to stress. We compared the associations of IL-18 with cortisol and clinical variables in adolescents with early-onset psychosis (EOP) aged 12-18 years and age-matched healthy controls (HC). METHOD: We measured serum IL-18, IL-18 binding protein (IL-18BP), IL-18 receptor accessory protein (IL-18RAP), IL-18 receptor 1 (IL-18R1) and cortisol, and calculated the IL-18/IL-18BP ratio in patients (n = 31) and HC (n = 60). Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale and depressive symptoms by the Mood and Feelings Questionnaire-Child version (MFQ-C). Bivariate correlation analysis was used to explore relationships between IL-18/IL-18BP ratio and cortisol, depression and other clinical characteristics. Hierarchical multiple linear regression analysis was used to assess their individual contributions to the variance of the IL-18/IL-18BP ratio. RESULTS: Patients had significantly higher IL-18 levels and IL-18/IL-18BP ratios than HC, but similar IL-18BP, IL-18RAP and IL-18R1. Both cortisol (R2 change = 0.05) and the MFQ-C score (R2 change = 0.09) contributed significantly to the variance in IL-18/IL-18BP ratios after controlling for confounders. CONCLUSION: We found increased IL-18 system activity in adolescents with EOP. Cortisol and depressive symptoms each contributed to the variance in the IL-18/IL-18BP ratio. Our findings support activation of inflammatory pathways in adolescent psychosis and suggest interactions between stress, inflammation and depressive symptoms in EOP.

Potential involvement of the interleukin-18 pathway in schizophrenia.

OBJECTIVE: Accumulating evidence implicates inflammatory cytokines in the development of psychiatric disorders, including schizophrenia (SZ). IL-18 is one of cytokines that plays a crucial role in immune response and neurodevelopment. We aimed to investigate potential genetic alterations of the cytokine system underpinning SZ. METHODS: We tested the association of genetic variants within the cytokine-cytokine receptor interaction (CCRI) pathway with SZ, using GWAS-derived data involving 768 adult SZ patients and 1348 controls, and replicated the association of IL18R1 rs1035130 with SZ in an independent sample of 1957 adult patients and 1509 controls. We compared expression levels of IL18, IL18R1 and IL18RAP in peripheral blood of a cohort of adolescent participants (<18 years), including 14 early-onset SZ patients and 13 healthy controls. Furthermore, we carried out a cis-eQTL (expression Quantitative Trait Loci) and a cis-mQTL (Methylation Quantitative Trait Loci) analysis for IL18R1 rs1035130. RESULTS: In the discovery stage, we detected association signals within two IL18 pathway genes, IL18R1 and IL18RAP, with the most significant marker being IL18R1 rs1035130 (P = 1.84E-7, OR = 0.70). In the validation stage, we found rs1035130 was associated with SZ (P = 0.028, OR = 0.89). Expressions of IL18 and IL18R1 were altered in blood of SZ patients compared with 13 controls. Furthermore, cis-QTL analyses indicated that rs1035130 was associated with an eQTL and 5 mQTLs. CONCLUSION: Our findings suggest the alteration of IL18 pathway may contribute to the psychopathology of SZ.

Increased expression of interleukin-18 receptor in blood cells of subjects with mild cognitive impairment and Alzheimer's disease.

Inflammation has been proposed as a leading force in neurodegeneration and Interleukin (IL)-18 is a pro-inflammatory cytokine which is suggested to be implicated in Alzheimer's disease (AD). However, the meaning of the IL-18 participation in this disease is still unclear. Since IL-18 activity is mediated by its heterodimeric receptor complex IL-18Rα/ß, we evaluated the presence of both IL-18R chains on peripheral blood cells of AD patients, as well as in individuals with Mild Cognitive Impairment (MCI), at increased risk to develop AD. More specifically, we compared the levels of CD14(+) monocytes and CD3(+) T-lymphocytes bearing IL-18Rα and ß chains in the two groups of patients with those in healthy control subjects, both before and after in vitro cell treatment with lipopolysaccharide (LPS). While no differences in the levels of monocytes and T-lymphocytes bearing IL-18Rα chain were found among the three groups, either in untreated and LPS-treated conditions, the IL-18Rß chain expression appeared differently regulated in MCI and AD patients, as compared to controls. In particular, the amount of IL-18Rß-bearing monocytes was similar among the three groups at unstimulated conditions, while after LPS treatment it was increased in MCI vs. controls. A significant increase of IL-18Rß-bearing T-lymphocytes was also observed in MCI and AD vs. controls, both in untreated and LPS-stimulated conditions. Our findings indicate that the expression of IL-18R complex on blood cells is perturbed in AD and even more markedly in its preclinical state of MCI, confirming that an increased peripheral activity of IL-18 may be involved in the early phase of AD pathophysiology.

Increased expression of interleukin-18 and its receptor in peripheral blood of patients with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a complex systemic disorder characterized by both local pulmonary and systemic inflammation. Many studies suggested that activation of circulating inflammatory cells and increased circulating levels of inflammatory cytokines occur in COPD. Interleukin (IL)-18 is a unique proinflammatory cytokine that mediates its effects by binding to the IL-18 receptor (IL-18R). In the present study, the expression of IL-18 in serum and IL-18R on peripheral blood T lymphocytes was analyzed. Enzyme-linked immunosorbent assay (ELISA) was used to determine the serum levels of IL-18 and interferon (IFN)-γ, and high sensitivity C-reactive protein (hsCRP) were measured by chemiluminiscent immunoassay. Expression of IL-18R was examined using a three-color flow cytometry method. In total, 120 subjects were recruited including 32 nonsmokers, 30 current smokers and 58 stable COPD patients. Serum levels of IL-18 and hsCRP were significantly higher in stable COPD patients than those in nonsmokers and current smokers. A significant negative correlation existed between pulmonary function and serum level of IL-18 rather than hsCRP in stable COPD patients. The proportions of IL-18Rα-expressing T lymphocytes and CD8(+) T lymphocytes were significantly higher in stable COPD patients than in nonsmokers and current smokers. The current study extended prior analyses by examining IL-18R expression in peripheral blood. The results suggested that IL-18/IL-18R system was active in peripheral blood of COPD patients.

[Expression of interleukin-18 and interleukin-18 receptor alpha chain of the peripheral white blood cells in immune thrombocytopenia].

OBJECTIVE: To detect the expression of interleukin (IL)-18 of the peripheral blood cells and IL-18 receptor alpha chain (IL-18Ralpha) on the surface of CD(3)(+) cells in patients newly diagnosed as immune thrombocytopenia (ITP) before medication and to explore the roles of IL-18 and IL-18Ralpha in the development of ITP. METHODS: Eighteen out-patients or inpatients with acute ITP accepting treatment in Qilu Hospital were enrolled in this study and 15 matching healthy subjects were taken as control. Plasma IL-18 level was detected with enzyme linked immunosorbent assay (ELISA), the expression of IL-18Ralpha on CD(3)(+) lymphocytes and total lymphocytes were measured with flow cytometry;T-bet and GATA-3 mRNA were measured with reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: The expression of IL-18 in acute ITP plasma was (468.57 + or - 141.62) ng/L and IL-18Ralpha on the surface of CD(3)(+) cells and lymphocytes were (8.50 + or - 3.16)% and (9.16 + or - 2.98)% respectively. The levels of IL-18 and IL-18Ralpha were increased in active ITP patients as compared with those in the controls (P < 0.05). The levels of IL-18 mRNA (0.12 + or - 0.02) and T-bet mRNA (0.07 + or - 0.02) were significantly increased in patients with active ITP as compared with those in the controls (P < 0.05), while GATA-3 mRNA (0.0039 + or - 0.0014) were significantly decreased in patients with active ITP (P < 0.05). The balance between T-bet and GATA-3 was significantly disturbed in ITP. CONCLUSIONS: Through the variation of the levels of gene and protein, our study showed that IL-18 and IL-18Ralpha might upregulate the expression of Th1-cytokines in ITP patients. It is also suggested that IL-18 has potential association with the development of ITP. Especially, it may provide a new treatment method for ITP by regulating the ratio of T-bet and GATA-3 and resuming the balance of Th1/Th2.