IL-12 and IL-23: master regulators of innate and adaptive immunity

Summary: Initiation of an effective immune response requires close interactions between innate and adaptive immunity. Recent advances in the field of cytokine biology have led to an increased understanding of how myeloid cell‐derived factors regulate the immune system to protect the host from infections and prevent tumor development. In this review, we focus on the function of interleukin (IL)‐23, a new member of the IL‐12 family of regulatory cytokines produced by activated macrophages and dendritic cells. We propose that IL‐12 and IL‐23 promote two distinct immunological pathways that have separate but complementary functions. IL‐12 is required for antimicrobial responses to intracellular pathogens, whereas IL‐23 is likely to be important for the recruitment and activation of a range of inflammatory cells that is required for the induction of chronic inflammation and granuloma formation. These two cytokines work in concert to regulate cellular immune responses critical for host defense and tumor suppression.     

Carotid and femoral B-mode ultrasound intima-media thickness measurements in adult post-coarctectomy patients.

AIM: Cardiovascular and cerebrovascular morbidity and mortality in adult post-coarctectomy patients is increased even after successful surgical repair of the aorta. B-mode ultrasound intima-media thickness (IMT), a validated marker for atherosclerosis and vascular disease risk, was used to measure pre-coarctatial carotid and post-coarctatial femoral arterial wall changes in these patients. METHODS: Measurements were done in 131 patients (mean age 31.6 y [SD 11.3 y]; 78 were normotensive, 53 were hypertensive) and in 26 controls (30.9 y [SD 9.4 y]). RESULTS: Age, serum lipids and smoking history were similar in patients and controls. Overall, IMT in patients and controls were similar (0.59 mm [SD 0.14 mm] and 0.59 mm [SD 0.08 mm]. In patients, carotid IMT was increased (0.67 mm [SD 0.12 mm] vs 0.61 mm [SD 0.08 mm] in controls: p=0.01); femoral IMT was decreased (0.48 mm [SD 0.09 mm] vs 0.57 mm [SD 0.07 mm]: p=0.001). In normotensive patients carotid IMT was not increased (0.64 mm [SD 0.12 mm] vs 0.61 mm [SD 0.08 mm]: p=0.2), but patients showed a higher SD. Carotid IMT in hypertensive patients was increased (0.72 mm [SD 0.12 mm] vs 0.64 mm [SD 0.11 mm] in normotensive patients: p<0.001). The femoral IMT in normo- and hypertensives patients were similar (0.48 mm [SD 0.09 mm] and 0.49 mm [SD 0.10 mm]: p=0.12). Carotid IMT in patients with aortic coarction and age at surgery were associated (r=0.36, p<0.0001), where femoral IMT is not. CONCLUSION: Early peripheral arterial wall damage is prominent in hypertensive post-coarctatial patients and is limited to pre-coarctatial conduits. The decreased femoral IMT in all patients may indicate a relatively low post-coarctatial blood pressure if pressure control is guided according to pre-coarctatial RR. Pre-coarctatial arterial wall change is less apparent in post-coarctectomy patients who have a controlled blood pressure and who had early surgical repair.     

Immunomodulatory role of endogenous interleukin-18 in gamma interferon-mediated resolution of replicative Legionella pneumophila lung infection

The in vivo role of endogenous interleukin-18 (IL-18) in modulating gamma interferon (IFN-gamma)-mediated resolution of replicative Legionella pneumophila lung infection was assessed using a murine model of Legionnaires' disease. Intratracheal inoculation of A/J mice with virulent bacteria (10(6) L. pneumophila organisms per mouse) resulted in induction of IL-18 protein in bronchoalveolar lavage fluid (BALF) and intrapulmonary expression of IL-18 mRNA. Real-time quantitative RT-PCR analysis of infected lung tissue demonstrated that induction of IL-18 in BALF preceded induction of IL-12 and IFN-gamma mRNAs in the lung. Blocking intrapulmonary IL-18 activity by administration of a monoclonal antibody (MAb) to the IL-18 receptor (anti-IL-18R MAb) prior to L. pneumophila infection inhibited induction of intrapulmonary IFN-gamma production but did not significantly alter resolution of replicative L. pneumophila lung infection. In contrast, blocking endogenous IL-12 activity by administration of anti-IL-12 MAb) alone or in combination with anti-IL-18R MAb inhibited induction of intrapulmonary IFN-gamma and resulted in enhanced intrapulmonary growth of the bacteria within 5 days postinfection. Taken together, these results demonstrate that IL-18 plays a key role in modulating induction of IFN-gamma in the lung in response to L. pneumophila and that together with IL-12, IL-18 regulates intrapulmonary growth of the bacteria.     

Adherence to evidence-based statin guidelines reduces the risk of hospitalizations for acute myocardial infarction by 40%: a cohort study.

AIMS: To investigate the 'real world' effectiveness of robust statin therapy, focusing on the effect of dose and early treatment discontinuation on the risk of hospitalization for acute myocardial infarction (AMI). METHODS AND RESULTS: In the PHARMO database, including among others drug-dispensing and hospital discharge records for more than two million subjects in the Netherlands, 59,094 new users of statins in the period 1 January 1991 until 31 December 2004, >or=18 years of age were identified. In these patients, exposure to statins, both in terms of persistence and dose, was determined over the first two treatment years. To determine the risk for AMI, patients were followed from this 2-year time point until the first hospital admission for AMI, death, or end of the study period. A total of 31,557 patients (53%) discontinued statin use within 2 years; 20 883 patients (35%) were persistent users with an average equipotent dose>or=4. A 30% reduction in risk of hospitalization for AMI with persistent statin use was observed. The protective effect increased with a higher dose (20 and 40% risk reduction with an equipotent doseor=4, respectively). CONCLUSION: These results show that statins are suboptimally used in real life for having the maximum benefit in terms of preventing AMI.     

Paraoxonase gene polymorphisms are associated with carotid arterial wall thickness in subjects with familial hypercholesterolemia

Human serum paraoxonase (PON) is a high density lipoprotein (HDL) associated enzyme capable of hydrolyzing lipid peroxides in vitro. PON has recently attracted attention as a protective factor against oxidative modification of LDL and may therefore play an important role in the prevention of the atherosclerotic process. Two frequent mutations at the paraoxonase gene locus (PON1) are the leucine (L allele)-->methionine (M allele) and the glutamine (Q allele)-->arginine (R allele) substitutions at residues 55 and 192, respectively. We have examined the influence of these two polymorphisms on carotid atherosclerosis in familial hypercholesterolemia (FH) patients. The allele frequencies of these two polymorphisms were determined by PCR and restriction fragment analysis, for both the FH population and healthy controls. High resolution B-mode ultrasound was used to assess intima-media wall thickness (IMT) of the carotid artery. No differences were found in allele frequencies between the FH and the control population. In FH patients, the LL, LM and MM genotypes at position 55 occurred in 86 (46.0%), 78 (41.7%) and 23 (12.3%) subjects, respectively, whereas the QQ, QR and RR genotypes at position 192 were found in 90 (48.1%), 79 (42.2%) and 18 (9.6%) individuals. When both polymorphisms were considered separately, no different carotid IMTs were found between the genotype groups. However, our data did show a significant association between the various genotypes of the combined polymorphisms at position 55 and 192 of PON1 and the carotid artery IMT in FH subjects. Subjects with the homozygous wildtype LL/QQ for paraoxonase had the highest mean carotid IMTs when compared to other genotypes, combined. Multiple regression analysis demonstrated age (beta=0.34, P<0.0001), total plasma cholesterol (beta=0.17, P=0. 0109) and the LL/QQ genotype of the PON1 gene (beta=0.22, P=0.0018) to be significant risk factors for carotid atherosclerosis in subjects with FH. The LL/QQ genotype could explain 5.3% of total variance of carotid IMT. In conclusion, this is the first study to report an independent association between the combined PON1 polymorphism genotypes and carotid wall thickness. The homozygous wildtype LL/QQ for PON1 may represent an additional risk factor for carotid atherosclerosis in subjects with FH.     

The effect of concentrated n-3 fatty acids versus gemfibrozil on plasma lipoproteins, low density lipoprotein heterogeneity and oxidizability in patients with hypertriglyceridemia

We evaluated in a double-blind randomized trial with a double-dummy design in 28 patients with primary hypertriglyceridemia, the effect of gemfibrozil (1200 mg/day) versus Omacor (4 g/day), a drug containing the n-3 fatty acids eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), on lipid and lipoprotein levels, low density lipoprotein (LDL) subfraction profile and LDL oxidizability. Both Omacor and gemfibrozil therapy resulted in a similar significant decrease in serum triglyceride (TG), very low density lipoprotein (VLDL) triglyceride and VLDL cholesterol concentrations and an increase in high density lipoprotein (HDL) and LDL cholesterol concentrations. The increase in LDL cholesterol was due to a significant increase in cholesterol content of the relatively buoyant LDL subfractions LDL1, LDL2 and LDL3, whereas the relative contribution of the dense LDL subfractions LDL4 and LDL5 to total LDL tended to decrease. So, both therapies resulted in a more buoyant LDL subfraction profile, reflected by a significant increase of the value of parameter K (+10.3% on Omacor vs. +26.5% on gemfibrozil therapy, gemfibrozil vs Omacor P>0.05). Cu(2+)-induced oxidation of LDL was measured by continuous monitoring of conjugated dienes. After 12 weeks of Omacor treatment LDL appeared more prone to oxidative modification in vitro than LDL after gemfibrozil treatment, as measured by the significantly decreased lag time, preceding the onset of the lipid peroxidation. In both groups the rate of oxidation did not change with therapy. The amount of dienes formed during oxidation increased significantly on Omacor treatment, but not on gemfibrozil treatment. Plasma thiobarbituric acid reactive substances were higher after Omacor and lower after gemfibrozil treatment, although not significantly. We conclude that both Omacor and gemfibrozil have favorable effects on lipid and lipoprotein concentrations and the LDL subfraction profile. However, Omacor increased the susceptibility of LDL to oxidation, whereas gemfibrozil did not affect the resistance of LDL to oxidative modification in vitro. The clinical relevance of these changes remains to be established in the light of other postulated favorable effects of n-3 fatty acids on the course of cardiovascular disease.