The role of IL-18 and IL-12 in the modulation of matrix metalloproteinases and their tissue inhibitors in monocytic cells

The matrix metalloproteinases (MMP) are enzymes crucial for the physiological patrol as well as pathological chemotaxis of immune cells to target tissues. The present study examined differential effects of pro-inflammatory [IL-18, IL-12 and tumor necrosis factor (TNF)-alpha] versus anti-inflammatory (IL-4) cytokines on the modulation of MMP and their endogenous tissue inhibitors (TIMP) expression in the U937 cell line. IL-18 and IL-12 separately and synergistically enhanced MMP-2, while TNF-alpha led to the elevation of MMP-9. All pro-inflammatory cytokines enhanced MT1-MMP expression and IL-4 suppressed TNF-alpha-induced MMP-9 expression. This study demonstrated that elevated IL-18 and IL-12, and related pro-inflammatory activity, may be associated with aberrant MMP activity, suggesting modulation of MMP expression using IL-12 and IL-18 antagonists as future therapeutic strategies to attenuate inflammatory and autoimmune disorders.     

HLA transgenic mice as models of human autoimmune diseases

MHC class II alleles have been linked to several human autoimmune diseases such as rheumatoid arthritis (RA), Type I diabetes, and multiple sclerosis (MS). Although the mechanisms by which expression of certain MHC class II molecules predispose an individual to a particular autoimmune disease are not known, it is clear that increased susceptibility is associated with the polymorphic regions unique to these predisposing HLA alleles. These polymorphic differences may influence susceptibility by selecting potential autoreactive T cells during thymic education. Alternatively, nonsusceptible alleles may either delete or fail to select these potential autoimmune T cells, thus reducing the possibility of developing disease. In the periphery, the unique specificity of the HLA molecule derived from a susceptible allele may then recognize and present an autoantigenic peptide or foreign peptide that may cross-react with an autoantigen, activating these autoreactive T cells and leading to disease. To dissect these possibilities and to determine the exact role of particular HLA-DR or DQ molecules in disease susceptibility, we have generated several lines of HLA-DR and DQ transgenic mice. In this review, we present data summarizing the functions of these HLA class II molecules using well-established mouse models for autoimmune diseases.     

HPV DNA in plasma of patients with cervical carcinoma.

BACKGROUND: HPV DNA has been detected in metastatic tumour and HPV plasma viraemia may indicate a poor prognosis and a high risk for metastasis. OBJECTIVE: Detection of HPV DNA in plasma of patients with cervical carcinoma. STUDY DESIGN: A cross-sectional study was done, wherein cervical biopsies and plasma samples were collected from 58 women with invasive cervical carcinoma, 10 women with cervical intraepithelial neoplasia (CIN) and 30 control women in the same age range. Polymerase chain reaction (PCR) was employed to detect the presence of HPV DNA. Samples positive for HPV DNA were typed by restriction fragment length polymorphism (RFLP). To confirm that the HPV sequence in plasma was identical to that in tissue, sequencing was done on all the paired plasma and tissue samples. RESULTS: All the 30 paired cervical tissue and plasma samples from the controls were negative for HPV DNA. HPV DNA was detectable in cervical tissues of 55 (94.8%) of 58 patients with invasive cervical carcinoma and in all 10 patients (100%) with CIN and in eight (11.8%) of the total 68 plasma samples from patients. All eight plasma samples were from women with invasive cervical carcinoma with three each in stages IIIB and IV and one each in stages IIB and IB, respectively. Of the eight positive samples, seven were typed as HPV-16 and 1 as HPV-58. HPV types detected in cervical tissue and plasma pairs from these eight patients correlated as revealed by RFLP and sequencing. A patient with stage IB cancer had detectable HPV DNA in the external iliac lymph node, removed at Wertheims hysterectomy, which was histopathologically free of tumour. The HPV type in the node, was the same as that present in the paired tissue and plasma sample. CONCLUSIONS: HPV DNA is detectable in the plasma of patients with advanced cervical cancer.     

Association of the dihydrolipoamide dehydrogenase gene with Alzheimer's disease in an Ashkenazi Jewish population.

Abundant biochemical evidence links deficient activity of mitochondrial alpha-ketoglutarate dehydrogenase with neuropathologically confirmed Alzheimer's disease (AD). Reduced alpha-ketoglutarate dehydrogenase activity has also been associated with anti-mortem measures of clinical disability. One of the genes encoding this complex, namely, DLD, lies within a chromosome 7 region that is in linkage disequilibrium with AD. We therefore examined the hypothesis that variation in DLD is associated with AD risk. Denaturing HPLC was used to search for sequence variations in the coding and flanking regions of all exons of DLD, but no abundant variants that alter protein sequence were found. However, four common SNPs were identified and genotyped in a case-control series of 297 Caucasians from New York City, including 229 residents of a Jewish nursing home. Logistic regression analysis was performed for the four-locus DLD genotype, sex, and ApoE4 status to determine the association of these independent variables with AD. Significant associations with AD were observed for ApoE4 (P < 10(-6)) and sex combined with DLD genotype (P = 0.013). The association with the DLD genotypes appears only in the male population in both the Caucasian series (P = 0.0009, n = 83) and the Ashkenazi Jewish subseries (P = 0.017, n = 49). The DLD genotype appears to operate independently of APOE in conferring AD risk.     

Aluminum welding fume-induced pneumoconiosis

Chronic exposure to high concentrations of fumes during aluminum arc welding causes a severe pneumoconiosis characterized by diffuse pulmonary accumulation of aluminum metal and a corresponding reduction in lung function. Aluminum fume-induced pneumoconiosis is a rarely reported entity, of which the true incidence is unknown. We report the clinical, radiographic, microscopic, and microanalytic results of 2 coworkers, employed by the same aluminum shipbuilding facility, who died of complications from this disease. Scanning electron microscopy and energy dispersive x-ray analysis of the exogenous particle content in the lung tissue of these cases revealed the highest concentrations of aluminum particles (average of 9.26 billion aluminum particles per cm(3) of lung tissue) among the 812 similar analyses in our pneumoconiosis database. One patient had an original clinical diagnosis of sarcoidosis but no evidence of granulomatous inflammation.     

Case report: glomus tumor of the colon

Glomus tumors are tumors of pericytic origin and are usually found in the distal extremities. Glomus tumors have rarely been reported in viscera. The authors report a glomus tumor of the colon that caused rectal bleeding in a 40-yr-old man and was biopsied and excised endoscopically. The histology and immunohistochemical profile of the tumor are described and the literature on visceral glomus tumors is reviewed.     

Expression of interleukin-18 in the lung after endotoxemia or hemorrhage-induced acute lung injury

Hemorrhage and endotoxemia are important risk factors for the development of acute lung injury. Interleukin (IL)-18 is a recently described cytokine released in its mature, active form after pro-IL-18 is cleaved by the IL-1 converting enzyme (ICE). IL-18 has multiple immunomodulating properties, including induction of interferon-gamma (IFN-gamma), IL-1beta, tumor necrosis factor-alpha, and intercellular adhesion molecule-1. To examine the possible involvement of IL-18 in acute lung injury, we examined its expression, as well as that of IFN-gamma, IL-12, and ICE, using murine hemorrhage or endotoxemia models. The amounts of IL-18 messenger RNA (mRNA) increased in the lung after hemorrhage or endotoxemia. However, only endotoxemia was associated with elevations in lung and plasma concentrations of IL-18 protein. ICE expression was increased in the lungs after endotoxemia but not after hemorrhage. Although IFN-gamma expression increased in the lungs after hemorrhage or endotoxemia, elevations in lung IL-12 mRNA levels were found only after endotoxemia. These results indicate that hemorrhage and endotoxemia induce different patterns of immunomodulatory cytokine expression in the lungs. In particular, differences in the expression of ICE after hemorrhage or endotoxemia may affect generation of the active forms of downstream cytokines, including IL-18. IFN-gamma expression in the lungs after hemorrhage appears to occur through a pathway independent of IL-12 and IL-18. IL-18 may play a role in modulating the development of acute lung injury after endotoxemia but not after hemorrhage.     

Platelet-activating factor (PAF)-dependent biochemical, morphologic, and physiologic responses of human platelets: demonstration of translocation of protein kinase C associated with protein phosphorylation

Platelet-activating factor (PAF) is a potent stimulus for platelet aggregation and secretion. PAF has been shown to stimulate the phosphatidylinositol (PI) pathway in platelets, which implies that PAF should activate protein kinase C. In this study, measurements of PI metabolites, the elevation of intracellular free calcium concentration, (Ca2+)i, the activation of protein kinase C, and the phosphorylation of platelet proteins (using a two-dimensional gel electrophoretic technique) were performed before and after the addition of 10(-8) M PAF to human platelets. These findings were correlated with morphologic changes in the platelets as determined by immunoelectron microscopic studies on the cytoskeleton and by X-ray analysis of dense bodies. The results show that PAF stimulates the production of PI metabolites and causes an increase in the membrane-associated activity of protein kinase C. These changes are accompanied by a rise in the (Ca2+)i and protein phosphorylation. The increase in protein kinase C activity reaches a maximum at approximately 60 s, a time frame that is consistent with the protein phosphorylation and the subsequent morphologic and secretory events. X-ray analysis revealed two types of dense bodies containing various amounts of calcium which appeared to be released sequentially after PAF activation. These results suggest that the protein phosphorylation that controls the physiologic events resulting from PAF activation of human platelets is catalyzed by protein kinase C.