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.     

Symptomatic hepatothorax presenting 25 years after penetrating thoracoabdominal injury

Hepatic herniation through the diaphragm is a rare finding. It generally occurs due to a congenital diaphragmatic abnormality or blunt trauma resulting in a diaphragmatic defect. Making the diagnosis is difficult, as there are few definitive clinical signs and chest radiograph (CXR) findings may be non-specific. To our knowledge, only a single case report exists of penetrating right diaphragm injury leading to hepatic herniation.A 42-year-old man presented to the emergency department of a regional hospital with hyperglycaemia and exertional dyspnoea. He was diagnosed with diabetes mellitus type 2. He gave a history of smoking for 15 pack-years, was negative for retroviral disease and had no history of pulmonary tuberculosis. He had no significant surgical history but reported being stabbed with a knife in 1995. The point of entry was below the level of the nipple in the right anterior axillary line. At the time, he was treated with an intercostal drain and discharged home.CXR showed a right-sided chest mass. We considered a differential diagnosis of pulmonary consolidation, diaphragm eventration or hepatothorax. Computerized tomography of the chest and abdomen demonstrated apparent intrathoracic extension of the right liver lobe and partial attenuation of the superior vena cava and right atrium due to a mass effect. The upper border of the liver abutted the aortic arch. Surgical treatment options were discussed. The patient declined surgery and will be followed up as an outpatient.     

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.