Fibrosing colonopathy is a recently described complication of cystic fibrosis, of unknown aetiology but possibly related to treatment with high-dose pancreatic enzyme supplements. We have used a whole gut perfusion technique to study subclinical gut inflammation in cystic fibrosis patients; concentrations of haemoglobin, IgG, albumin, alpha-1-antitrypsin, granulocyte elastase, IL1 beta, and IL8 were measured in whole gut lavage fluid: 23 tests were performed in 17 children with cystic fibrosis (20 elective tests, three lavages to treat distal intestinal obstruction syndrome (DIOS)). None has had fibrosing or haemorrhagic colitis. There were 12 tests in control children with constipation or precolonoscopy. Moderately abnormal results were obtained for many of the parameters studied, in specimens from all the cystic fibrosis children; however there were no significant differences between tests on high-dose and low-dose enzyme supplements of the same brand in the five children who had duplicate tests performed electively. The lavage fluid specimens from two cystic fibrosis children were strikingly abnormal in all tests apart from haemoglobin and alpha-1-antitrypsin. These were two of the three children with DIOS, and were also the only cases in the series taking Nutrizym 22. These data suggest that the majority of cystic fibrosis children, including those on high-dose enzyme supplements, do not have clinically significant colitis, but that there is subclinical mucosal inflammation in a minority (two of 17 in this series), for which DIOS and/or Nutrizym 22 treatment may be risk factors. Alternatively, inflammation and dysmotility in the proximal colon may be directly produced by a drug or other agent, producing a clinical syndrome indistinguishable from DIOS. Tests for indices of inflammation in gut lavage fluid offer a new approach to the detection and measurement of iatrogenic intestinal and colonic injury.

Since patients with primary biliary cirrhosis (PBC) have evidence of abnormal function of the immune system, we evaluated production of various cytokines by peripheral blood mononuclear cells (PBMCs) and monocytes from patients with this disease, using an enzyme-linked immunosorbent assay. The mean amounts of production of tumor necrosis factor alpha(TNF alpha), interleukin 1 beta (IL1 beta), and interferon-gamma (IFN-gamma) by PBMCs from patients with PBC tended to be increased in cultures in the presence of stimulating agents in comparison with controls, but there was no significant difference because of a wide scatter of results. Monocytes from PBC patients also tended to produce higher amounts of TNF alpha and IL1 beta than control monocytes did, although the percentage of monocytes in PBMCs was similar in PBC and controls. A significant correlation was found between TNF alpha production and IL1 beta production in PBC patients. The number of TNF alpha or IFN-gamma positive infiltrating mononuclear cells detected by immunohistochemical staining in liver biopsy sections correlated with the production of these cytokines by PBMCs in vitro. However, cytokine production did not correlate with serum biochemical or hepatic histologic findings, except for serum alkaline phosphatase values. In patients with type B chronic active hepatitis, IL1 beta and IFN-gamma production was similar to controls, while TNF alpha production tended to be enhanced. Thus the cytokines studied here may play some role in the pathogenesis of PBC.

OBJECTIVE

To investigate the effects of maternal lead (Pb) exposure on the learning and memory ability and expression of interleukin1-β (IL1-β), tumor necrosis factor (TNF-α) and beta amyloid protein (Aβ) in cerebral cortex of mice offspring.

METHODS

Pb exposure initiated from beginning of gestation to weaning. Pb acetate administered in drinking solutions was dissolved in distilled deionized water at the concentrations of 0.1%, 0.5% and 1% groups, respectively. On the PND21, the learning and memory ability were tested by water maze test and the Pb levels were also determined by graphite furnace atomic absorption spectrometry. The expression of IL1-β, TNF-α and Aβ in cerebral cortex was measured by immunohistochemistry and western blotting.

RESULTS

The Pb levels in blood and cerebral cortex of all exposure groups were significantly higher than that of the control group (P<0.05). In water maze test, the performances of 0.5% and 1% groups were worse than that of the control group (P<0.05). The expression of IL1-β, TNF-α and Aβ was increased in Pb exposed groups than that of the control group (P<0.05).

CONCLUSIONS

The high expression of IL1-β, TNF-α and Aβ in the cerebral cortex of pups may contribute to the impairment of learning and memory associated with maternal Pb exposure.

Malformin-A1, a cyclic pentapeptide of microbial origin, antagonized in a competitive manner the binding of 125I-IL1 beta (interleukin-1 beta) to human monocytes and cultured human umbilical vein endothelial cells (HUVEC) with IC50 values (doses which reduce specific binding by 50%) of 250 +/- 80 and 230 +/- 25 nM, respectively (N = 3). IL1 increased in a dose-dependent manner the expression of tissue factor, a ubiquitous membrane-anchored glycoprotein that initiates blood coagulation at the surface of HUVEC and human monocytes. Malformin-A1 strongly inhibited IL1-induced tissue factor expression in HUVEC and monocytes with IC50 values of 420 +/- 35 and 105 +/- 25 nM, respectively (N = 3), and reduced IL1-induced expression of intercellular adhesion molecule-1 (ICAM-1, CD54) on HUVEC (IC50 = 125 +/- 18 nM) (N = 4). These observations demonstrate that malformin-A1 recognizes and blocks IL1 beta binding to its receptor sites on monocytes and endothelial cells and protects these cells from IL1-induced procoagulant changes.

Idiopathic pulmonary fibrosis (IPF) involves collagen deposition that results in a progressive decline in lung function. This process involves activation of Smad2/3 by transforming growth factor (TGF)-β and Wnt signaling pathways. Collagen Triple Helix Repeat-Containing-1 (Cthrc1) protein inhibits Smad2/3 activation. To test the hypothesis that Cthrc1 limits collagen deposition and the decline of lung function, Cthrc1 knockout (Cthrc1-/-) and wild-type mice (WT) received intratracheal injections of 2.5 U/kg bleomycin or saline. Lungs were harvested after 14 days and Bronchoalveolar lavage (BAL) TGF-β, IL1-β, hydroxyproline and lung compliance were assessed. TGF-β was significantly higher in Cthrc1-/- compared to WT (53.45 ± 6.15 ng/mL vs. 34.48 ± 11.05) after saline injection. Bleomycin injection increased TGF-β in both Cthrc1-/- (66.37 ± 8.54 ng/mL) and WT (63.64 ± 8.09 ng/mL). Hydroxyproline was significantly higher in Cthrc1-/- compared to WT after bleomycin-injection (2.676 ± 0.527 μg/mg vs. 1.889 ± 0.520, P = 0.028). Immunohistochemistry of Cthrc1-/- lung sections showed intracellular localization and activation of β-catenin Y654 in areas of tissue remodeling that was not evident in WT Lung compliance was significantly reduced by bleomycin in Cthrc1-/- but there was no effect in WT animals. These data suggest Cthrc1 reduces fibrotic tissue formation in bleomycin-induced lung fibrosis and the effect is potent enough to limit the decline in lung function. We conclude that Cthrc1 plays a protective role, limiting collagen deposition and could form the basis of a novel therapy for pulmonary fibrosis.

Sterile inflammation is considered critical in the pathogenesis of diabetic nephropathy (DN). Here we show that Fetuin-A (FetA) or lipopolysaccharide (LPS) exacerbate palmitic acid-induced podocyte death, which is associated with a strong induction of monocyte chemoattractant protein-1 (MCP-1) and keratinocyte chemoattractant (KC). Moreover, blockage of TLR4 prevents MCP-1 and KC secretion and attenuates podocyte death induced by palmitic acid alone or combined with FetA. In addition, inhibition of interleukin-1 (IL-1) signaling by anakinra, a recombinant human IL-1Ra, or a murinized anti-IL-1β antibody attenuates the inflammatory and ultimate cell death response elicited by FetA alone or combined with palmitic acid. In vivo short-term therapy of diabetic DBA/2J mice with an anti-IL1-β antibody for 4 weeks prevented an increase in serum FetA and considerably decreased urinary tumor necrosis alpha (TNF-α), a known risk factor for DN progression. In summary, our results suggest that FetA similarly to LPS leads to an inflammatory response in podocytes, which exacerbates palmitic acid-induced podocyte death and our data imply a critical role for IL-1β signaling in this process. The study offers the rational for prolonged in vivo studies aimed at testing anti-IL-1β therapy for prevention and treatment of DN.

BACKGROUND

During adolescence, peer victimization is a potent type of social stressor that can confer enduring risk for poor mental and physical health. Given recent research implicating inflammation in promoting a variety of serious mental and physical health problems, this study examined the role that peer victimization and cognitive vulnerability (i.e. negative cognitive styles and hopelessness) play in shaping adolescents' pro-inflammatory cytokine responses to an acute social stressor.

METHODS

Adolescent girls at risk for psychopathology (n = 157; Mage = 14.73 years; SD = 1.38) were exposed to a laboratory-based social stressor before and after which we assessed salivary levels of three key pro-inflammatory cytokines - interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α).

RESULTS

As hypothesized, adolescents with greater peer victimization exposure exhibited greater increases in IL-6 and IL1-β in response to the laboratory-based social stressor. Moreover, for all three cytokines individually, as well as for a combined latent factor of inflammation, peer victimization predicted enhanced inflammatory responding most strongly for adolescents with high levels of hopelessness.

CONCLUSIONS

The findings reveal a biological pathway by which peer victimization may interact with cognitive vulnerability to influence health in adolescence.

The effects of a recombinant human interleukin-1 (IL-1) receptor antagonist (IL-1ra) and a recombinant human soluble IL-1 receptor (sIL-1R) on cytokine-induced intercellular adhesion molecule-1 (ICAM-1) expression in a human glioblastoma cell line and a neuroblastoma cell line were determined. Cells were incubated with IL-1 beta, tumor necrosis factor (TNF) alpha and interferon (IFN) gamma. Cells were also tested under identical conditions with an IL-1 beta synthetic peptide fragment (IL-1 beta 208-240) previously shown to possess biological activity. IL-1 beta, TNF alpha and IFN gamma potentiated ICAM-1 expression in both cell lines in a dose-related manner. The IL-1 beta 208-240 fragments, corresponding to the rabbit, rat and human sequences, enhanced ICAM-1 expression in glioblastoma cells at high doses. ICAM-1 expression induced by IL-1 beta, rabbit IL-1 beta 208-240 and human IL-1 beta 208-240 was blocked by the IL-1ra, while TNF alpha- and IFN gamma-induced ICAM-1 expression were not. ICAM-1 expression induced by IL-1 beta and human IL-1 beta 208-240 was also blocked by the sIL-1R. Our findings suggest that IL1 beta 208-240 acts as an IL-1 beta agonist in enhancing ICAM-1 expression in vitro and that this effect is receptor-mediated.

In this study, we were interested to compare the responsiveness to growth factors, NGF, b-FGF and EGF and cytokines, IL1 beta, and TNF-alpha, in late passages (74-79) C6 glial cells committed astrocytes and astrocytes of advanced passages (26-28) in cultures derived from aged mouse cerebral hemispheres (MACH). Cultures were grown in either DMEM or chemically defined medium (CDM/TIPS) in order to test the effects of growth factors or cytokines. The activity of glutamine synthetase (GS), a marker for astrocytes, was used as a test parameter. We found that treatment with growth factors increased GS activity in both glial cell culture systems with the exception of EGF in C-6 glial cells. Treatment with cytokines markedly decreased GS activity in the late passage C6 glial cells whereas only TNF-alpha had a similar effect on MACH astrocytes. In view of the generally opposite effects of growth factors and cytokines on GS activity, we speculate that these molecules which are also endogenously present in glial cells may play a role in the maintenance of cellular homeostasis.

OBJECTIVE

A group of the proinflammatory and chemotactic cytokines (chemokines) has been considered as an important factor in the pathomechanism of different bacterial diseases, among them the common Helicobacter pylori infection. Experimental results obtained with gastric biopsy samples of H. pylori positive patients, and with H. pylori infected tumor originated gastric cell lines indicated that these cytokines have essential roles in the development and maintenance of the immune response and inflammation of the gastric mucosa during H. pylori infection. Although the mRNA expression was shown in these biopsy samples and cell lines, it is not yet proved that the normal gastric mucosal epithelial cells themselves express these cytokines. The establishment of a gastric surface mucous cell line with non-tumor origin (GSM06), and the usage of Helicobacter felis as a model of the classic H. pylori infection gave us the possibility to check this question.

METHODS

in this study GSM06 cells were infected with different numbers (10(5), 10(6), 10(7), 10(8), 10(9) bacterium/ml medium) of H. felis for two different time periods (2, 4 h). Cells treated with medium only were used as control. Then the mRNA expression of the following cytokines was measured by RT-PCR method in the GSM06 cells: proinflammatory cytokine IL1-beta, and chemokine RANTES, eotaxin, MCP-1, MIP1-alpha and MIP1-beta.

RESULTS

we found that neither mRNA of the investigated cytokines was expressed constitutively, however the GSM06 cells expressed the mRNA of each cytokine during H. felis infection.

CONCLUSIONS

our results prove that normal gastric surface mucous epithelial cells express immunologically active peptides during H. felis infection. We may suppose that the epithelial cells of the gastric mucosa contribute to the immune response and inflammation by expressing proinflammatory (IL1-beta) and chemotactic (RANTES, eotaxin, MCP-1, MIP1-alpha and beta) cytokines during H. pylori infection in human.

OBJECTIVE

To investigate serum inflammatory factors in patients with idiopathic choroidal vascularization (CNV), including vascular endothelial growth factor (VEGF), tumor necrosis factor alpha (TNFα), Interleukin1-beta (IL1-β), IgG, IgA, IgM, IgE, 50% hemolytic unit of complement (CH50), complement C3, complement C4 and C reactive protein (CRP).

METHODS

21 patients and 20 normal individuals were recruited. They received comprehensive ophthalmic examinations. Serous concentrations of VEGF, TNFα, IL1-β were assayed by ELISA, and the concentrations of other serum factor were assayed by immunonephelometry.

RESULTS

The mean serum VEGF level in the CNV group was significantly greater than that in the control group (p=0.025). The median level of IgE in the CNV group was significantly lower than that in the control group (p=0.006). Statistical analysis revealed no significant difference in the levels of TNFα, IL1-β, IgG, IgA, IgM, CH50, C3, C4 or CRP between the two groups.

CONCLUSIONS

The possible roles of these factors and mechanisms of idiopathic CNV formation were analyzed. Serum VEGF and IgE levels may play an important role in the formation of idiopathic CNV.

The production of interleukin 1 beta (IL1 beta) in lipopolysaccharide (LPS) stimulated monocytes was inhibited by 98% using antisense phosphorothioate oligonucleotides complementary to the 5' untranslated and exon 6 regions of IL1 beta mRNA. A sense phosphorothioate oligonucleotide failed to inhibit IL1 beta production. The inhibition of IL1 beta synthesis was not due to reduced cell viability and [35S]methionine incorporation showed that it could not be accounted for by an overall inhibition in protein synthesis. Tumour necrosis factor (TNF) and IL1 alpha production was also inhibited but to a lesser extent than IL1 beta. The use of antisense phosphorothioate oligonucleotides to inhibit IL1 production should enable the complex pathways of IL1 regulation to be elucidated and provide information on the biological role of these cytokines.

BACKGROUND

Cytokines (IL-1beta and TNF) generated by WBCs during storage of PLT concentrates have been associated with febrile nonhemolytic transfusion reactions.

METHODS

This study was undertaken to investigate whether there is an association between the polymorphisms of IL1B -511C/T and +3953C/T, IL1RN intron 2 VNTR and TNFA-308G/A genes and the increase of cytokines during the storage of PLT concentrates produced by plasma-rich PLTS (PRP-PC) or apheresis PLTs.

RESULTS

Thirty PRP-PCs were studied and a progressive increase of IL-1beta and TNF during storage was revealed. IL1-beta and TNF levels were inversely correlated with the content of PLTs in PRP-PCs detected on Day 3 (p = 0.004) and Day 5 (p = 0.019), but not on Day 7. There was association of IL1B-511T polymorphism and IL-1beta levels (Day 5, p = 0.063, only tendency and on Day 7, p = 0.038, significant). There was no association of the other polymorphisms (IL1B+3953C/T, IL1RN intron 2 and TNFA-308G/A) with their respective cytokines.

CONCLUSIONS

The great variation of cytokine levels in the plasma of PLT concentrates (PCs) during storage may also be caused by cytokine gene polymorphisms, as well as WBC contamination, material that the bags are made of, and storage time, as previously described.

OBJECTIVE

Twelve patients with superficial papillary transitional cell carcinoma of the bladder (pTa, pT1) were treated with six consecutive weekly intravesical instillations of Rubratin (in a dose of 1.5, 3.0, or 4.5 mg), a cell wall skeleton preparation of Nocardia rubra (NCW). The main objective of this study was to look for local immunomodulating effects of NCW and in the first four patients the effect on a marker lesion was also investigated.

METHODS

Local immunostimulation in all 12 patients was determined by (1) measurement of cytokine induction [interleukin 1 beta (IL1 beta), IL2, IL6, and tumor necrosis factor alpha (TNF alpha)], (2) leukocyte influx into the urine, and (3) phenotypic analysis of the lymphocyte fraction of these leukocytes.

RESULTS

Significantly elevated levels of Rubratin-induced IL1 beta (P < 0.001), IL2 (P < 0.001), IL6 (P < 0.01), and TNF alpha (P < 0.001) were found compared to control pretherapy levels. Rubratin also induced leukocyte influx into the urine. Fluorescence-activated cell sorter (FACS) analysis of the urinary leukocytes indicated T-cell activation (IL2 receptor and HLA-DR expression), while in two out of five patients the CD4/CD8 ratios were increased. Urinary cytokine induction by Rubratin was comparable with cytokine induction observed in nonresponding bacillus Calmette-Guérin (BCG) patients (recurrent tumor within 6 months), but less compared with responding BCG patients (no recurrent tumor within 6 months). Clinical results showed no response on the marker lesion and in five out of eight patients early recurrence was found after complete transurethral resection (TUR) of the bladder tumors. This biological response modifier caused no local or systemic side effects at the doses used.

CONCLUSIONS

Although local immunostimulation by intravesical Rubratin administration can be induced, the amount of immunocompetent cells attracted to the bladder is not as high as observed in BCG-responding patients, resulting in lower amounts of cytokines produced. This could also explain the lack of clinical efficacy.

Sensory input to different cortical areas differentially varies across the light-dark cycle and likely is responsible, in part, for activity-dependent changes in time-of-day differences in protein expression such as Fos. In this study we investigate time-of-day differences between dark (just before light onset) and light (just before dark onset) for the number of immunoreactive (IR) neurons that stained for tumor necrosis factor alpha (TNFalpha), interleukin-1 beta (IL1 beta), nerve growth factor (NGF), the neuronal nuclear protein (NeuN) and Fos in the rat somatosensory cortex (Sctx) and visual cortex (Vctx). Additionally, astrocyte IL1 beta-IR in the Sctx and Vctx was determined. TNFalpha and IL1 beta, as well as the immediate early gene protein Fos, were higher at the end of the dark phase (2300 h) compared to values obtained at the end of the light phase (1100 h) in the Sctx and Vctx. IL1 beta-IR in Sctx and Vctx astrocytes was higher at 2300 h than that observed at 1100 h. . In contrast, the number of NGF-IR neurons was higher in the Vctx than in the Sctx but did not differ in time. However, the density of the NGF-IR neurons in layer V was greater at 2300 h in the Sctx than at 1100 h. NeuN-IR was higher at 2300 h in the Sctx but was lower at this time in the Vctx compared to 1100 h. These data demonstrate that expressions of the molecules examined are dependent on activity, the sleep-wake cycle and brain location. These factors interact to modulate time-of-day expression.

Tumor cells are protected from antibody-dependent complement-mediated lysis by membrane-bound regulators of complement activation (m-RCA). m-RCA are expressed on uveal melanoma cells. We determined whether cytokine treatment affects expression of m-RCA on these cells in vitro. m-RCA expression on uveal melanoma cell lines was studied by flow cytometry, using monoclonal antibodies directed against CD46, CD55, and CD59. Cytokines studied were interferon-alpha (IFN-alpha), IFN-gamma, interleukin-1B (IL-1B), IL-12, and tumor necrosis factor-alpha (TNF-alpha). All three m-RCA were expressed on the uveal melanoma cell lines (CD59>)CD46>CD55), although in variable amounts. With a few exceptions, the cytokines had no effect on m-RCA expression. CD55 expression was not influenced by any of the cytokines. IFN-gamma downregulated expression of CD46 on one cell line (p < 0.01). TNF-alpha upregulated CD59 expression on two of the five cell lines (p < 0.012 and p < 0.001, respectively), which effect was dose dependent. IFN-alpha, IFN-gamma, <em>IL1</em>-<em>beta</em>, <em>IL1</em>2, and TNF-alpha had limited effects on m-RCA expression on uveal melanoma cells in vitro.

The humoral cross-talk between bone and fat is an area of increasing interest. We investigated the expression and regulation of the bone-acting cytokines; bone morphogenetic protein 2 (BMP2), connective tissue growth factor (CTGF), osteoprotegerin (OPG), and transforming growth factor beta (TGFB1). Subcutaneous adipose tissue was aspirated from lean, healthy women. Tissue samples were incubated with interleukin 1-β (IL1-β), tumor necrosis factor-α (TNF-α), cortisol, troglitazone, IL1-β + troglitazone, or vehicle. Gene expression in the adipose tissue was analyzed using qPCR and protein levels in the incubation media were analyzed using ELISA. OPG expression and secretion was diminished by 40.8% and 43.1% respectively, by cortisol, and OPG expression was diminished by 67.5% by troglitazone (p<0.05). The proinflammatory cytokines IL1-β and TNF-α significantly increased the expression of CTGF (p<0.05) by 65.1% and 101.3%, respectively, and the expression and secretion of OGP by 62.3-165.8% (p<0.05). This interleukin 1-β mediated increase in CTGF- and OPG expression and secretion was ameliorated by troglitazone. Troglitazone and related drugs are known to have adverse effects on bone. We suggest that this could be mediated via altered cytokine production in adipose tissue. Moreover, obese individuals have a low-grade inflammation in their adipose tissue and have higher bone mineral density than lean individuals. We suggest that this inflammation may increase the expression and secretion of OPG and CTGF and thereby increase BMD. In conclusion, bone acting cytokines are produced in the adipose tissue and may affect bone through endocrine mechanisms.

A bovine pituitary extract (BPE) induces thymidine incorporation into human thymic epithelial cells (TEC) in vitro. Previous data demonstrated that its effects resulted in epithelial cell replication and suggested that the active component of BPE was likely to be a growth factor, different from epidermal growth factor (EGF) and interleukin 1 (IL1). In this report we present evidence to identify the active component of BPE as a fibroblast growth factor (FGF) family member, based upon several criteria: a) Purified bovine and human recombinant FGF also enhanced TEC proliferation in vitro. b) Neutralization studies showed antigenic similarities between BPE and basic FGF. c) Biochemical analytical studies allowed purification of BPE by its affinity for heparin with elution at 3M NaCl, and gel filtration sizing yielded a 73 KD molecule with which basic FGF co-eluted. The isoelectric point was found to be between 6.3 and 6.6 and this is the only finding not consistent with the characterization of basic FGF as the factor responsible for the activity of BPE on TEC proliferation.

Probiotic lactic acid bacteria are known for their ability to modulate the immune system. They have been shown to inhibit inflammation in experiments with animal models, cell culture, and clinical trials. The objective of this study was to elucidate the anti-inflammatory potential of Lactobacillus plantarum Lp62, isolated from cocoa fermentation, in a cell culture model. Lp62 inhibited IL-8 production by Salmonella Typhi-stimulated HT-29 cells and prevented the adhesion of pathogens to these epithelial cells. The probiotic strain was able to modulate TNF-α, IL1-β, and IL-17 secretion by J774 macrophages. J774 activation was reduced by coincubation with Lp62. PBMC culture showed significantly higher levels of CD4(+)CD25(+) T lymphocytes following treatment with Lp62. Probiotics also induced increased IL-10 secretion by mononuclear cells. L. plantarum Lp62 was able to inhibit inflammatory stimulation in epithelial cells and macrophages and activated a tolerogenic profile in mononuclear cells of healthy donors. These results indicate this strain for a possible application in the treatment or prevention of inflammatory diseases.

Synthetic glycolipid, maltose hexastearate (MHS), like LPS or lipid A is a B cell mitogen for outbred Swiss mice, inbred C3H/HeN and C3H/HeJ X C3H/HeN F1 hybrid but not for C3H/HeJ mice. MHS administered i.p. (10 micrograms) to Swiss, C3H/HeN, C3H/HeJ and C3H/HeJ X C3H/HeN F1 hybrid mice confers within 90 min an increased ability in the spleen cell populations such that they exhibit increased incorporation of 3H thymidine into cellular DNA in vitro. The spleen cells of MHS treated mice also respond in vitro more vigorously than controls to a T cell mitogen (Con A) but not at all differently from controls to a B cell mitogen (LPS). The stimulated cells are sensitive to anti theta serum + C' (experiment done with Swiss mice) and the Lyt 1,1 monoclonal antibody + C' (experiment done with C3H/HeN mice), indicating them functionally to be of T-helper variety. Unlike MHS, lipid A administration i.p. resulted in MHS like response in C3H/HeN but not in C3H/HeJ mice. MHS action has been traced to an induction of IL1 release by macrophages of MHS treated animals by chromatographic analysis of macrophage derived supernatants. IL1, in turn, according to the prevalent concepts would stimulate immature T cells to become mature IL2 producer cells, allowing T helper cell proliferation through IL2 release.

Clinical scientists from eight European countries and China gathered in the ancient Chinese capital of Xi'an on April 26-28, 2001 to discuss collaboration on a modern approach to gastric cancer prevention. Participants at the First Sino-European Workshop on Immunogenetics and Pathogenesis of Gastric Cancer presented their most up-to-date research results on topics ranging from epidemiology and immune mechanisms to Helicobacter pylori and vaccine development. Researchers then formed groups with their Chinese or European counterparts to plan future research endeavors which will benefit Chinese and European populations alike. After 3 years of organization between the Institute of Digestive Diseases of the Fourth Medical University in Xi'an, China and the Laboratory of Immunogenetics, VU University Medical Center in Amsterdam, the first workshop came into being under the joint sponsorship of the Commission of the European Union, National Natural Science Foundation of China and the Institute of Digestive Diseases, Xi'an, China. As gastric cancer is the most prevalent malignant tumor in China, the workshop was of special significance to the Chinese researchers and to the Chinese population in general. During the workshop, presentations on the epidemiology of gastric cancer showed that this disease is in fact common the world over: it is the second most common cancer next to lung cancer and about 1 million new cases were diagnosed in 2000. Three-quarters of the cases of gastric cancer occur in Asia, and approximately 80% of these cases are in China and Japan. Genetic factors and environmental factors such as diet and H. pylori infection play a role in gastric carcinogenesis. As a recognized cause of gastric cancer, H. pylori was the subject of various presentations ranging from immunological studies, molecular analysis of strains and pathogenesis to vaccine development. Specific areas of discussion included bacterial-epithelial interactions in H. pylori infection, epidemiology in China, global distribution of vacA and cagA genotypes, new evidence for host factors, nonsteroidal antiinflammatory drugs and H. pylori as independent risk factor for gastric cancer, new diagnostic techniques for H. pylori using serum levels of pepsinogen I, and autoimmune processes in corpus atrophy. Vaccine development using a variety of strategies against H. pylori was the subject of an entire session of talks. Oral immunization with urease with Escherichia coli heat labile enterotoxin was shown to be safe and immunogenic in humans as a mucosal adjuvant. Results of a study using attenuated Salmonella typhimurium as a vehicle for DNA-mediated immunization in mice were also presented. A final presentation discussed an ongoing trial comparing strain variability in the vacA and cagA gene sequences and disease expression between H. pylori infection in Europe and China. Researchers also discussed the role of IL1 gene family and TNF gene polymorphisms in gastric pathology and various immune mechanisms involved in gastric cancer, such as down-regulation of NF kappa B, IL-1 and IL-1RA, cyclooxygenase signalling, and identification of MGAg antibodies. An interactive discussion followed each presentation and ideas and suggestions were provided. According to specialty, the presenters were then assigned to groups of four or five to make plans for joint research projects. A number of international and Chinese observers were present, including representatives from the European Commission, the World Health Organization and the Chinese National Center for Biotechnology Development, and offered input on the financial feasibility of such projects.

Cecal ligation and puncture (CLP) is the sepsis model that more closely resembles the human pathology, but it is likely to cause suffering to experimental animals. However, it is not clear whether the use of analgesia may affect some parameters evaluated in experimental sepsis research. Therefore, we investigated the effects of fentanyl and tramadol in experimental sepsis in the rat. The following parameters were evaluated: body temperature, body weight, water and food ingestion, mortality, analgesia, blood leukocytes, mean arterial blood pressure, vascular reactivity to phenylephrine, lung myeloperoxidase activity, and plasma levels of IL1-β, glutamic-oxaloacetic, glutamic-pyruvic, lactate, creatinine and urea. While producing significant analgesia, the opioids modify minimally the parameters, with the exception of sepsis-induced hypotension and mortality. Although fentanyl and tramadol can minimize pain and the general suffering of animals submitted to CLP surgery, their effects on cardiovascular parameters as well as in the mortality indicate that their use in experimental sepsis must be done with caution and with all the proper control groups.

Primary gonadal failure frequently occurs in male patients with serious illness. This has suggested that activation of the immune system may affect the endocrine function of the testis. Most previous studies have evaluated the effects of individual cytokines on testosterone (T) production but with conflicting results. The present study was performed to compare the effects on Leydig cell function of a mixture of cytokines found in macrophage conditioned media (MCM), with that of individual recombinant cytokines. The MCM was found to contain an acid stable, heat labile, 16.5 kD factor(s) which significantly decreased the production of testosterone (T), dihydrotestosterone (dHT), adenosine 3':5'-cyclic monophosphate (cAMP), and guanosine 3':5'-cyclic monophosphate (cGMP). The MCM had no effect on the specific binding of human chorionic gonadotropin (hCG) but decreased the activity of 3-beta-hydroxysteroid dehydrogenase (3-beta-HSD) (a regulated Leydig cell enzyme). Neither tumor necrosis factor alpha (TNF alpha) interleukin 1 alpha (IL1 alpha), interleukin 1 beta (IL1 beta), interleukin 2 (IL2), interleukin 6 (IL6), or human interferon alpha,beta (IFN alpha,beta) had a similar effect. These results show that the cytokines or other factor(s) contained in MCM are potent regulators of T production, which could be important in understanding the low serum T levels associated with serious illness.

Ischemic stroke (IS) is a complex disease with sex differences in epidemiology, presentations, and outcomes. However, the sex-specific mechanism underlying IS remains unclear. The purpose of this study was to identify key genes contributing to biological differences between sexes. First, we downloaded the gene expression data of GSE22255 from Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were identified using R software and related packages. Second, DEGs were separately analyzed by Gene Ontology enrichment and pathways analyses. Third, protein-protein interaction (PPI) network was constructed to further investigate the interactions of DEGs. A total of 123 DEGs were identified between sexes, including 8 upregulated and 115 downregulated genes. In the PPI network, ten key genes were identified, including IL1α, IL1β, IL6, IL8, CXCL1, CXCL2, CXCL20, CCL4, ICAM1, and PTGS2. Functional enrichment analysis revealed that these genes were mainly enriched in biological processes of immune response and apoptotic process, also in pathways of TNF and NOD-like receptor signaling. In conclusion, the above ten genes may have a protective effect on IS females through their direct or indirect involvement in biological processes of immune response and apoptotic process, as well as in TNF and NOD-like receptor signaling pathways. The results of this study may help to gain new insights into the sex-specific mechanisms underlying IS females and may suggest potential therapeutic targets for disease treatment.