OBJECTIVE

We compared the effects of exercise intensity (EI) on the cytokine response to an acute bout of running.

METHODS

Ten males (mean ± SD VO(2max)= 56.2 ± 8.1 mL·min(-1)·kg(-1)) completed three, counterbalanced, 8-d trials. After three control days, on day 4, participants completed 60 min of running at 55%, 65%, and 75% VO(2max). The cytokines tumor necrosis factor (TNF)-α, interleukin-1β (IL-1β), IL-6, and IL-1 receptor antagonist (ra), and creatine kinase were measured during and for 3 h after exercise and on four follow-up days (FU1-FU4).

RESULTS

RER was higher at 75% V(O2max) compared with both 55% (P < 0.001) and 65% (P < 0.01) VO(2max). IL-1β was undetectable in six participants. There was a small (18%-27%) increase in TNF-α during exercise but no effect of EI. IL-6 concentrations peaked at the end of exercise, with a greater increase at 75% VO(2max), resulting in higher concentrations at the end of exercise and at 30 min after exercise compared with 55% (P < 0.001) and 65% VO(2max) (P < 0.01). IL-1ra concentrations peaked at the end of exercise at 75% VO(2max), resulting in higher (P < 0.05) concentrations at 1-2 h after exercise compared with 55% and 65% VO(2max). Creatine kinase was increased at FU1 and FU2, but there was no effect of EI.

CONCLUSIONS

Sixty minutes of treadmill running at 75% VO(2max) results in a greater increase in IL-6 but not TNF-α compared with 55% and 65% V(O2max). The higher IL-1ra concentrations at 75% VO(2max) might be related to the higher IL-6 concentrations that precede them.

Taurolidine (Geistlich Pharm, AG, Wolhusen, Switzerland), a derivative of the amino acid taurine, is commonly used in some parts of the world as an adjunctive therapy for various infections. Its mechanism of action is thought to be related to its antimicrobial properties, including its ability to interfere with some of the biological activities of endotoxin (lipopolysaccharide, LPS). For example, taurolidine has been shown to protect animals against endotoxic shock and death. In this study we examined the ability of taurolidine to block LPS-induced tumor necrosis factor (TNF) and <em>interleukin</em> 1 (IL-1) synthesis in human peripheral blood mononuclear cells (PBMC) from <em>27</em> donors. We observed a dose-dependent reduction in the synthesis of these two cytokines when taurolidine was preincubated with LPS before being added to PBMC. This reduction was independent of the molar ratio of taurolidine to LPS but was related to the concentration of taurolidine present in the PBMC cultures. There was a 80 to 90% reduction in total IL-1 and TNF synthesis induced by LPS at concentrations of taurolidine of 40 to 100 micrograms/mL; the vehicle was without effect. Following a 30-min preincubation with PBMC, taurolidine could be washed from the cells and still suppress cytokine synthesis induced by LPS. Using release of lactic acid dehydrogenase, 100 micrograms/mL of taurolidine was not toxic for PBMC. Taurolidine also reduced IL-1 and TNF synthesis induced by the Staphylococcus aureus-derived toxic shock syndrome toxin-1 as well as that induced by nontoxic heat-killed Staphylococcus epidermidis organisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Telmisartan, an angiotensin II type 1 receptor antagonist, was reported to be a partial agonist of peroxisome proliferator-activated receptor-gamma. Although peroxisome proliferator-activated receptor-gamma activators have been shown to have an anti-inflammatory effect, such as inhibition of cytokine production, it has not been determined whether telmisartan has such effects. We examined whether telmisartan inhibits expression of <em>interleukin</em>-6 (IL-6), a proinflammatory cytokine, in vascular smooth muscle cells. Telmisartan, but not valsartan, attenuated IL-6 mRNA expression induced by tumor necrosis factor-alpha (TNF-alpha). Telmisartan decreased TNF-alpha-induced IL-6 mRNA and protein expression in a dose-dependent manner. Because suppression of IL-6 mRNA expression was prevented by pretreatment with GW9662, a specific peroxisome proliferator-activated receptor-gamma antagonist, peroxisome proliferator-activated receptor-gamma may be involved in the process. Telmisartan suppressed IL-6 gene promoter activity induced by TNF-alpha. Deletion analysis suggested that the DNA segment between -150 bp and -<em>27</em> bp of the IL-6 gene promoter that contains nuclear factor kappaB and CCAAT/enhancer-binding protein-beta sites was responsible for telmisartan suppression. Telmisartan attenuated TNF-alpha-induced nuclear factor kappaB- and CCAAT/enhancer-binding protein-beta-dependent gene transcription and DNA binding. Telmisartan also attenuated serum IL-6 level in TNF-alpha-infused mice and IL-6 production from rat aorta stimulated with TNF-alpha ex vivo. These data suggest that telmisartan may attenuate inflammatory process induced by TNF-alpha in addition to the blockade of angiotensin II type 1 receptor. Because both TNF-alpha and angiotensin II play important roles in atherogenesis through enhancement of vascular inflammation, telmisartan may be beneficial for treatment of not only hypertension but also vascular inflammatory change.

We previously have described a model of multiple sclerosis (MS) in which constitutive expression of murine <em>interleukin</em> (IL)-2 by herpes simplex virus type 1 (HSV-1) (HSV-IL-2) causes central nervous system (CNS) demyelination in different strains of mice. In the current study, we investigated whether this HSV-IL-2-induced demyelination can be blocked using recombinant viruses expressing different cytokines or by injection of plasmid DNA. We have found that coinfection of HSV-IL-2-infected mice with recombinant viruses expressing IL-12p35, IL-12p40 or IL-12p35+IL-12p40 did not block the CNS demyelination, and that coinfection with a recombinant virus expressing interferon (IFN)-γ exacerbated it. In contrast, coinfection with a recombinant virus expressing IL-4 reduced demyelination, whereas coinfection of HSV-IL-2-infected mice with a recombinant HSV-1 expressing the IL-12 heterodimer (HSV-IL-12p70) blocked the CNS demyelination in a dose-dependent manner. Similarly, injection of IL-12p70 DNA blocked HSV-IL-2-induced CNS demyelination in a dose-dependent manner and injection of IL-35 DNA significantly reduced CNS demyelination. Injection of mice with IL-12p35 DNA, IL-12p40 DNA, IL-12p35+IL-12p40 DNA or IL-23 DNA did not have any effect on HSV-IL-2-induced demyelination, whereas injection of IL-<em>27</em> DNA increased the severity of the CNS demyelination in the HSV-IL-2-infected mice. This study demonstrates for the first time that IL-12p70 can block HSV-IL-2-induced CNS demyelination and that IL-35 can also reduce this demyelination, whereas IFN-γ and IL-<em>27</em> exacerbated the demyelination in the CNS of the HSV-IL-2-infected mice. Our results suggest a potential role for IL-12p70 and IL-35 signaling in the inhibition of HSV-IL-2-induced immunopathology by preventing development of autoaggressive T cells.

<em>Interleukin</em> (IL)-<em>27</em> is an IL-12-related cytokine that can promote both anti- and pro-inflammatory immune responses. This study investigated the potential role of IL-<em>27</em> in autoimmune diabetes. We detected a high level of IL-<em>27</em> in diabetic NOD mice. In addition, blockade of IL-<em>27</em> significantly delayed the onset of diabetic splenocyte-transferred diabetes, while IL-<em>27</em>-treated diabetic splenocytes promoted the onset of the disease, compared with untreated controls. Furthermore, IL-<em>27</em> up-regulated pro-inflammatory cytokines IFN-gamma and IL-17 and down-regulated anti-inflammatory cytokines IL-4, TGF-beta, and IL-10 secreted by diabetic splenocytes. These results demonstrate a pathogenic role of IL-<em>27</em> in T cell-mediated autoimmune diabetes.

IL-<em>27</em> is a recently identified heterodimeric cytokine produced in response to microbial and host derived inflammatory cues. Initial studies indicated that IL-<em>27</em> promotes the generation of Th1 responses required for resistance to intracellular infection and unveiled the molecular mechanisms mediating this effect. However, subsequent work uncovered a role for IL-<em>27</em> in the suppression of Th1 and Th2 responses. Thus, by discussing its pleotropic functions in the context of infection-induced immunity and by drawing parallels to fellow IL-6/IL-12 family cytokines, this review will attempt to reconcile the pro- and anti-inflammatory effects of IL-<em>27</em>.

OBJECTIVE

This article compares the pharmacokinetics, toxicity, and clinical efficacy of high-dose intravenous, low-dose intravenous, and intermediate-dose subcutaneous recombinant interleukin-2 (rIL-2) regimens in patients with measurable metastatic renal cell carcinoma.

METHODS

This trial began as a two-arm randomized study comparing two bolus intravenous rIL-2 regimens. High-dose (720,000 IU/kg) and low-dose (72,000 IU/kg) rIL-2 were administered every 8 hours for up to 15 consecutive doses. Later, a third arm of outpatient subcutaneous rIL-2 (week 1: 250,000 IU/kg/day for 5 of 7 days; weeks 2-6: 125,000 IU/kg/day for 5 of 7 days) was added, and only concurrently randomized patients were compared. A sample of patients underwent pharmacokinetic studies of serum IL-2 levels following their first dose. Accrual to this study is ongoing and results are preliminary.

RESULTS

In the two-arm comparison of high-dose versus low-dose intravenous rIL-2, 116 and 112 patients have been randomized, respectively, and the median follow-up is 52 months. Low-dose rIL-2 induced significantly less hypotension, thrombocytopenia, malaise, pulmonary toxicity, and neurotoxicity than high-dose rIL-2. The initial overall response rate (partial plus complete responses) was 19% with high-dose rIL-2 and 10% with low-dose rIL-2. Responses to high-dose rIL-2 tended to be more durable. With 54 to 56 patients randomized per arm in the three-arm comparison, the high-dose intravenous, low-dose intravenous, and subcutaneous outpatient rIL-2 regimens have produced response rates of 16%, 4%, and 11%, respectively. Subcutaneous rIL-2 therapy was infrequently associated with grade 3 or 4 toxicity (similar to low-dose intravenous rIL-2 therapy). Survival data remain incomplete with median follow-up in the three-arm trial at 27 months.

CONCLUSIONS

The optimal IL-2 regimen for treating metastatic renal cell carcinoma is not known. Alternative regimens with much less acute toxicity than high-dose IL-2 can cause regression of renal cell carcinoma, but duration of therapy, chronicity of symptoms, and quality-of-life issues may be important in properly evaluating the tolerability of different regimens. Because the main benefit of IL-2 therapy is not its initial response rate but its induction of durable, complete responses, further accrual and follow-up will be necessary to compare properly the impact of these regimens on patient survival.

This study investigated the effect of geldanamycin post-treatment on the development of secondary brain injury and neurological deficits in a mouse model of intracerebral hemorrhage. CD-1 mice received stereotactic injection of collagenase type VII into the right basal ganglia. Treatment groups were administered 1 mg/kg (low dose) or 10 mg/kg (high dose) of geldanamycin. Mice were euthanized at two time-points: 24 h or 72 h. Blood-brain-barrier permeability, brain edema, and neurobehavioral deficits were assessed. Additionally, the effects of geldanamycin on heat shock protein <em>27</em> and 72; tumor necrosis factor-alpha and <em>interleukin</em> 1 beta expressions were evaluated. High dose geldanamycin significantly attenuated blood-brain barrier disruption and brain edema after intracerebral hemorrhage. Neurobehavioral outcomes were significantly improved in some parameters by high dose treatment. Molecular results showed a marked increase in heat shock protein 72 expression in ipsilateral brain of geldanamycin treated groups with a reduction in the pro-inflammatory tumor necrosis factor-alpha.

CONCLUSIONS

Geldanamycin post-treatment is neuroprotective in the mouse model of intracerebral hemorrhage. Geldanamycin administration results in reduction of inflammation, preservation of blood-brain-barrier and amelioration of neurobehavioral deficits after an insult possibly by upregulation of heat shock protein 72.

OBJECTIVE

Which inflammation biomarkers detected in the vaginal fluid are most informative for identifying preterm delivery (PTD) risk?

CONCLUSIONS

Elevated interleukin (IL)-6 at mid-trimester was associated with increased odds of spontaneous PTD at <35 weeks and with PTD plus histologic chorioamnionitis (HCA), and had the greatest sensitivity for detecting these two PTD subtypes.

BACKGROUND

Maternal and/or fetal inflammation play a role in some preterm deliveries, therefore inflammation biomarkers might help to identify women at greater risk.

METHODS

We examined 1115 women from the Pregnancy Outcomes and Community Health Study, a cohort study conducted from September 1998 through June 2004, for whom data were available on mid-pregnancy inflammatory biomarkers.

METHODS

At enrollment at 16-27 weeks gestation, vaginal fluid samples were collected from a swab and 15 eluted biomarkers were measured using the Meso Scale Discovery multiplex electrochemiluminescence platform. Associations of biomarkers with PTD were examined, according to clinical circumstance, week at delivery and presence/absence of HCA. Weighted logistic regression was used to determine odds ratios (OR) and 95% confidence intervals (CI) adjusted for race. Sensitivity and specificity were compared between individual and multiple biomarkers, identified by a bootstrapping method.

RESULTS

Elevated IL-6 (>75th percentile) displayed the strongest association with spontaneous PTD <35 weeks (OR 2.3; CI 1.3-4.0) and PTD with HCA (OR 2.8; CI 1.4-6.0). The sensitivity of IL-6 to detect spontaneous PTD <35 weeks or PTD with HCA was 0.43 and 0.51, respectively, while specificity was 0.74 and 0.75, respectively. IL-6 plus IL1β, IL-6r, tumor necrosis factor-alpha or granulocyte-macrophage colony-stimulating factor increased specificity (range 0.84-0.88), but decreased sensitivity (range 0.28-0.34) to detect both PTD subtypes. Results were similar when a combination of IL-6 and bacterial vaginosis (BV) was explored. Thus, the use of multiple biomarkers did not detect PTD subtypes with a greater sensitivity than IL-6 alone, and IL-6 is a specific but non-sensitive marker for the detection of spontaneous PTD.

CONCLUSIONS

Our ability to find small effect size associations between PTD and inflammation biomarkers (OR <2.0) might have been limited by the modest number of less common PTD subtypes in our population (e.g. spontaneous delivery <35 weeks, PTD accompanied by HCA) and by relatively higher variability for some cytokines, for example tumor necrosis factor-α, IL-12p70, IL-10 and granulocyte-macrophage colony-stimulating factor, that are less stable and commonly undetectable or detectable at low levels in human vaginal secretions.

CONCLUSIONS

Larger studies are needed to further explore a role of inflammation biomarkers in combination with other risk factors, including specific BV-associated organisms, for the prediction of PTD subtypes.

BACKGROUND

This work was supported by the National Institute of Child Health and Human Development, National Institute of Nursing, March of Dimes Foundation, Thrasher Research Foundation and Centers for Disease Control and Prevention. The authors have no conflicts of interest.

Tumor-infiltrating lymphocytes (TIL) were isolated from 22 human primary and metastatic liver tumors, and expanded in vitro in the presence of either <em>interleukin</em>-2 (IL-2, 100 U/ml) plus tumor necrosis factor alpha (TNF alpha, 1000 U/ml), IL-2 (1000 U/ml) plus IL-4 (1000 U/ml) or IL-2 (1000 U/ml) alone. TIL proliferated in culture in 20/22 cases. Among different cytoline combination, TNF alpha and IL-2 were most effective in promoting the outgrowth of CD3+CD8+T lymphocytes (mean +/- SEM: 90% +/- 5) in the cultures of TIL from primary liver tumors. Cytotoxicity against autologous tumor cells was demonstrated in all early cultures of TIL from primary liver cancers in the presence of IL-2 plus TNF alpha. In contrast, cultures of TIL derived from colon cancer metastatic to liver had significantly lower levels of autotumor cytotoxicity and proportions of CD3+CD8+ cells (40% +/- 13) than those of TIL from primary liver tumors. The addition on day 0 of interferons (alpha or gamma) to TIL cultured in the presence of TNF alpha and IL-2, significantly augmented cytotoxicity against autologous tumor. In contrast, incubation of TIL in the presence of IL-4 and IL-2 did not result in increased autotumor responses in the cultures of TIL from primary liver tumors. The expansion (-fold) of TIL (day 30) cultured in the presence of IL-2 alone compared to that in the presence of TNF alpha and IL-2 was significantly greater for hepatocellular carcinoma (median, 280 vs 260) than for autologous peripheral blood lymphocytes (36 vs <em>27</em>), cholangiocarcinoma (42 vs 51) or TIL from metastatic colon cancer (39 vs 30). Outgrowth of TIL in IL-2 plus TNF alpha offers an opportunity for in vitro enrichment in cells with autotumor cytotoxicity in primary liver tumors. However, this cytokine combination was unable to promote and sustain growth of autotumor effectors from TIL in metastatic liver cancer.

Peritoneal mesothelial cells are uniquely located to regulate cellular events in the peritoneal cavity and are an important source for various cytokines and growth factors. This study was conducted to analyze the capacity of human peritoneal mesothelial cells (HPMCs) to synthesize and release basic fibroblast growth factor (bFGF) and to characterize its regulation by inflammatory cytokines. HPMCs constitutively synthesized and released considerable amounts of bFGF as detected by a specific immunoassay. Almost 80% of bFGF (1547 +/- 173 pg/10(5) cells) was localized intracellularly. Approximately 20% of the bFGF (357 +/- <em>27</em> pg/10(5) cells) was associated with extracellular matrix components on the HPMC surface. Small amounts of bFGF (<1%) were detectable in tissue culture supernatants (8.4 +/- 1.4 pg/10(5) cells). Treatment of HPMCs with <em>interleukin</em>-1beta (IL-1beta; 1 ng/ml) resulted in a significant increase in bFGF production. The intracellular bFGF content showed a rapid but only transient increase, which was significant above background levels after 24 hours (41% increase; P < 0.05). This increase in intracellular bFGF concentration was associated with an induction of the release of bFGF. Within 96 hours, the release of bFGF to the cell surface and into the supernatant increased by 58% (564 +/- 52.4 pg/10(5) cells; P < 0.01) and by 214% (26.4 +/- 3.2 pg/10(5) cells; P < 0.001), respectively. Neither tumor necrosis factor-alpha nor interferon-gamma affected bFGF synthesis by HPMCs. Stimulation of HPMCs with IL-1beta increased steady-state levels of bFGF-specific mRNA. Immunohistochemical analyses of peritoneal tissue revealed constitutive expression of bFGF by HPMCs. This in situ expression proved to be most pronounced in areas of serosal inflammation in activated HPMCs. Our study demonstrates that HPMCs synthesize and release significant amounts of bFGF and that the expression of this growth factor is significantly up-regulated by the proinflammatory cytokine IL-1beta. The data support the view that HPMCs are key regulators of abdominal disease processes such as peritonitis, peritoneal fibrosis, or peritoneal tumor metastasis.

After birth, host defences must be recruited to manage the transition from an almost sterile to a normal environment. The present study was undertaken to evaluate the relationship between cytokine plasma levels and phagocyte burst in mothers and neonates during the peripartal period. Plasma levels of <em>interleukin</em> (IL)-1, IL-6, tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and granulocyte-macrophage colony-stimulating factor (GM-CSF) and whole blood superoxide anion (.O2-) generation were evaluated in <em>27</em> healthy mothers, 16 undergoing vaginal delivery (VD) and 11 elective caesarean section (ECS) and in their babies. Blood specimens were taken from the mothers at the beginning of labour, during labour, immediately after delivery and 4 days later in the VD group, and before anaesthesia, immediately after delivery and 4 days later in the ECS group; neonatal samples were taken at birth (cord blood) and 4 days later. After delivery by VD, these mothers had higher plasma levels of IL-1 beta, IL-6, IFN-gamma and higher .O2- generation than those delivered by ECS. IL-6 plasma levels and .O2- generation were higher in babies born by VD than in those born by ECS. A statistically significant correlation between IL-6 plasma levels and .O2- release was observed in cord blood of babies born by VD (r = 0.69; p < 0.006). The study demonstrates that labour plays an important role in modulating host defences in the newborn.

Complement receptor 1 (CR1/CD35) levels on erythrocytes and related CR1 polymorphisms have been associated with response to falciparum malaria in populations inhabiting malaria-endemic regions. Differences in disease association profiles of its low expression alleles have been observed in populations from different regions of the world. We analyzed the influence of CR1 levels and associated SNPs on susceptibility/resistance to falciparum malaria in Indian populations. Two CR1 SNPs [exon 22 (A/G) and intron <em>27</em> (A/T)] define the low expression (L) CR1 allele in populations inhabiting a Plasmodium falciparum-endemic and a nonendemic region of India. Populations of the endemic region have very low red blood cell surface CR1 levels and higher frequencies of the exon 22 and intron <em>27</em> mutant L alleles. Whereas low CR1 levels correlated with susceptibility to severe malaria in the nonendemic region, high CR1 levels were associated with manifestation of disease in the endemic region. In addition, the exon 22 L allele was a risk factor for severe malaria in the nonendemic region. Absence of correlation between levels of tumor necrosis factor-alpha, interferon-gamma, and <em>interleukin</em>-6 with CR1 levels in patients with severe disease indicated that RBC CR1 levels in individuals are not the major determinants of pro-inflammatory cytokine release during infection. Our results are interpreted in the context of differences in the pathogenesis of severe malaria in the malaria-endemic and nonendemic region.

BACKGROUND

The authors previously identified and compared alterations in gene expression in the myocardia of patients with deteriorating heart failure who underwent left ventricular assist device (LVAD) implantation with those of patients with stable end-stage failure (ESF). We hypothesized that matrix metalloproteinases (MMPs) and their endogenous inhibitors, the tissue inhibitors of MMPs (TIMPs), would be implicated in the mechanisms that underlie deteriorating heart failure.

METHODS

Gridded macro-array filters were used to provide a broad overview of MMP and TIMP mRNA expression in heart failure. Precise mRNA levels of TIMP1, MMP1, and beta-spectrin were determined using quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) of myocardial samples from <em>27</em> patients with deteriorating heart failure who underwent LVAD implantation, from 17 patients with stable ESF who underwent elective heart transplantation, and from 28 donor organs with good hemodynamic function.

RESULTS

Gridded macro-arrays analysis of pooled failing heart samples determined that TIMP1 mRNA was the most readily detectable TIMP in failing myocardium. Quantitative RT-PCR showed that expression levels in individual patients were similar in patients with stable ESF (1.00 +/- 0.24, n = 17) and in donor organ samples (1.49 +/- 0.22, n = 28) but were significantly increased in the deteriorating heart failure group (5.38 +/- 0.32, n = 26, p < 0.0001 compared with patients with ESF). Similarly, MMP1 levels did not differ between donor and ESF groups but increased in the deteriorating failure group (6.04 +/- 0.50, n = <em>27</em>, p < 0.001 compared with the ESF group). Levels of beta-II spectrin were the same in all 3 groups. Both TIMP1 and MMP1 showed positive correlation with each other and with previously determined levels of mRNA for both interleukin-1beta (IL-1beta) and IL-6 in this patient series when considering all patients individually, but neither correlated with tumor necrosis factor alpha.

CONCLUSIONS

Patients with deteriorating heart failure have increased expression of TIMP1 and MMP1 mRNA. Correlation with pro-inflammatory cytokines suggests common pathways of regulation and potential activation by IL-6 and IL1-beta.

Quantification of <em>27</em> cytokines following cerebral wounding was performed for wound age estimation. The cytokines evaluated included <em>interleukin</em> (IL)-1alpha, IL-1beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IL-12 p40, IL-12 p70, IL-15, IL-17, IL-18, basic fibroblast growth factor (bFGF), granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), Interferon-gamma (IFN-gamma), keratinocyte derived cytokine (KC), leukemia inhibitory factor (LIF), macrophage-colony stimulating factor (M-CSF), monokine inducible by interferon gamma (MIG), macrophage inflammatory protein (MIP)-1 alpha, MIP 2, platelet-derived growth factor BB (PDGF BB), regulated upon activation, normal T-cell expressed, and secreted (Rantes), tumor necrosis factor-alpha (TNF-alpha), and vascular endothelial growth factor (VEGF). The proliferation of glial cells as well as the infiltration of inflammatory cells were also evaluated. Although astroglia proliferated from 72 hours post-injury, inflammatory cell dynamics were generally steady. Among cytokines analyzed in the present study, IL-1beta, IL-5, IL-6, IL-12 p40, G-CSF, IFN-gamma, KC, LIF, MIP2, and PDGF BB increased during the early phase of cerebral wound healing, and M-CSF increased during the middle phase, while IL-15, IL-18, and MIG increased during the late phase. In contrast, IL-1alpha, IL-10, IL-12 p70, and TNF-alpha were suppressed throughout the cerebral wound healing process. Based on our findings, quantitative cytokine analyses at the cerebral wound site may be a useful tool for wound age estimation. Further, this study suggests that multiplex data gained from the same sample using a single methodology demonstrates highly accurate cytokine interactions during the process of cerebral wound healing.

OBJECTIVE

The relationship of plasma cytokine levels to infection, core temperature, and to one another in patients with thermal injury was examined.

BACKGROUND

The response to infection has been associated with cytokines such as interleukin 1 beta (IL1 beta), interleukin 6 (IL6), and tumor necrosis factor alpha (TNF alpha), and these cytokines have been studied in various inflammatory diseases. The authors previously reported that patients with thermal injury have elevated IL1 beta and IL6 plasma levels and that these cytokines may play different roles in the response to thermal injury.

METHODS

IL1 beta, IL6, and TNF alpha were measured by enzyme-linked immunosorbent assay (ELISA) in serial samples of plasma from 27 patients.

RESULTS

IL6 and TNF alpha levels were increased in severely infected patients as compared to patients who remained free of infection, and the IL6 level was higher in infected patients who died than those who survived. There was no apparent relationship between IL1 beta levels and infection. IL6 and IL1 beta were positively correlated with core temperature. The correlations between IL6 and IL1 beta, between IL6 and TNF alpha, and between TNF alpha and IL1 beta were significant.

CONCLUSIONS

These results suggest that IL6 and TNF alpha play a role in the response of burned patients to infection.

OBJECTIVE

Other than age, the risk factors for postherpetic neuralgia are not well established. We studied whether the concentration of interleukin 8 in the cerebrospinal fluid is associated with the risk of postherpetic neuralgia.

METHODS

We enrolled 170 patients more than 50 years old who had a typical painful and nontrigeminal herpetic rash. Patients were treated with acyclovir; no corticosteroids were given. Cerebrospinal fluid was taken for analysis of interleukin 8 during and at full crusting of the herpetic rash. Age, sex, comorbid conditions, prodromal pain, localization and severity of herpetic rash, number of skin lesions, and degree of pain were recorded. We used multivariate logistic regression modeling to identify significant predictive factors. Receiver operating characteristic (ROC) curves were evaluated to determine the contribution of each factor.

RESULTS

Six months after healing, 31 patients (18%) had postherpetic neuralgia; 27 patients still had it after 1 year. Only three variables-age (odds ratio [OR] = 2.7 per 10-year increase; 95% confidence interval [CI]: 1.2 to 6.2), acute pain (OR = 1.8 per unit increase in visual analog scale; 95% CI: 1.2 to 2.8), and interleukin 8 concentration in the cerebrospinal fluid at full crusting of the herpetic rash (OR = 1.6 per 20-microg/L increase; 95% CI: 1.3 to 2.0)-were significant predictors of postherpetic neuralgia at 1 year. Interleukin 8 concentration also had the highest area under the ROC curve at these evaluation points (P <0.001).

CONCLUSIONS

Our results suggest that interleukin 8 concentration in the cerebrospinal fluid at full crusting of herpetic rash may be useful for identifying patients who are likely to develop intractable postherpetic neuralgia.

Crohn disease (CD) and ulcerative colitis (UC) are chronic forms of inflammatory bowel disease (IBD) whose pathogenesis is only poorly understood. Estrogens have a complex role in inflammation and growing evidence suggests that these hormones may impact IBD pathogenesis. Here, we demonstrated a significant reduction (p < 0.05) of estrogen receptor (ER)β expression in peripheral blood T lymphocytes from CD/UC patients with active disease (n = <em>27</em>) as compared to those in remission (n = 21) and healthy controls (n = 29). Accordingly, in a subgroup of CD/UC patients undergoing to anti-TNF-α therapy and responsive to treatment, ERβ expression was higher (p < 0.01) than that observed in not responsive patients and comparable to that of control subjects. Notably, ERβ expression was markedly decreased in colonic mucosa of CD/UC patients with active disease, reflecting the alterations observed in peripheral blood T cells. ERβ expression inversely correlated with <em>interleukin</em> (IL)-6 serum levels and exogenous exposure of both T lymphocytes and intestinal epithelial cells to this cytokine resulted in ERβ downregulation. These results demonstrate that the ER profile is altered in active IBD patients at both mucosal and systemic levels, at least in part due to IL-6 dysregulation, and highlight the potential exploitation of T cell-associated ERβ as a biomarker of endoscopic disease activity.

The pathogenesis of Helicobacter pylori-associated disorders is strongly dependent on a specialized type IV secretion system (T4SS) encoded by the cag pathogenicity island (PAI). Cytotoxin-associated gene A (CagA) is the only known H. pylori protein translocated into the host cell followed by tyrosine phosphorylation through host protein kinases. H. pylori induces cellular processes which are either PAI- or CagA-dependent (e.g., cell motility), PAI-dependent, but CagA-independent (e.g., <em>interleukin</em>-8 release), or PAI- and CagA-independent (e.g., cyclooxygenase-2 release). Here, we investigated H. pylori strains mutated in single PAI genes of the wild type strain Hp26695 and their effects on cell motility. We found 17 gene products out of <em>27</em> PAI genes playing a superordinated role and five PAI-encoded proteins exhibiting a clearly critical role in motogenic host cell responses, whereas the remaining five PAI gene products had no significant influence on the motogenic response in reaction to H. pylori infection. This study clearly demonstrated that H. pylori-induced cell motility and invasive growth involve type IV secretion system-dependent signalling as well as translocated and phosphorylated CagA. These findings reveal a deeper insight in to the meaning of the T4SS of H. pylori for host cell motility.

BACKGROUND

To study transcription factor signaling pathways that mediate cardiac allograft vasculopathy, we used mice with targeted gene deletion of signal transducer and activator of transcription (STAT)4 and STAT6 as recipients in our mouse cardiac transplant model of chronic rejection.

RESULTS

At day 55 after transplantation, cardiac grafts placed into STAT4 -/- (n=10) had reduced frequency (24+/-2%) and severity (9+/-4%) of vascular occlusion compared with wild-type controls (n=7, frequency 70+/-12% [P<0.001], severity 25+/-6% [P<0.05]). This decrease was associated with reduced intragraft expression ((32)P RT-PCR and immunohistochemistry) of the Th1 signature cytokines interferon-gamma (P<0.001) and <em>interleukin</em> (IL)-2 (P<0.001). Furthermore, cardiac grafts in STAT4 -/- had fewer infiltrating CD45(+) mononuclear cells (99+/-<em>27</em> cells/mm(3) compared with 551+/-168 cells/mm(3) in wild-type controls [P<0.05]) and reduced expression of P-selectin (P<0.001) and E-selectin (P<0.01) ligand, recently shown to regulate Th1 cell recruitment. In contrast, in grafts placed into STAT6 -/- (n=11), the development of cardiac allograft vasculopathy (frequency 62+/-8%, severity 28+/-6%) and Th2 cytokine profiles (IL-4, IL-10) were comparable to those in wild-type controls.

CONCLUSIONS

Hence, we show that immune responses mediated by STAT4, but not STAT6, contribute to the development of cardiac allograft vasculopathy. We speculate that when present, STAT4-mediated signaling pathways may promote cardiac allograft vasculopathy by directing Th1-specific lymphocyte recruitment, activation, and effector functions.

Vascular smooth muscle cell (VSMC) migration is an important cellular event in multiple vascular diseases, including atherosclerosis, restenosis, and transplant vasculopathy. Little is known regarding the effects of anti-inflammatory <em>interleukins</em> on VSMC migration. This study tested the hypothesis that an anti-inflammatory Th2 <em>interleukin</em>, <em>interleukin</em>-19 (IL-19), could decrease VSMC motility. IL-19 significantly decreased platelet-derived growth factor (PDGF)-stimulated VSMC chemotaxis in Boyden chambers and migration in scratch wound assays. IL-19 significantly decreased VSMC spreading in response to PDGF. To determine the molecular mechanism(s) for these cellular effects, we examined the effect of IL-19 on activation of proteins that regulate VSMC cytoskeletal dynamics and locomotion. IL-19 decreased PDGF-driven activation of several cytoskeletal regulatory proteins that play an important role in smooth muscle cell motility, including heat shock protein-<em>27</em> (HSP<em>27</em>), myosin light chain (MLC), and cofilin. IL-19 decreased PDGF activation of the Rac1 and RhoA GTPases, important integrators of migratory signals. IL-19 was unable to inhibit VSMC migration nor was able to inhibit activation of cytoskeletal regulatory proteins in VSMC transduced with a constitutively active Rac1 mutant (RacV14), suggesting that IL-19 inhibits events proximal to Rac1 activation. Together, these data are the first to indicate that IL-19 can have important inhibitory effects on VSMC motility and activation of cytoskeletal regulatory proteins. This has important implications for the use of anti-inflammatory cytokines in the treatment of vascular occlusive disease.

We carried out an open, non-randomized phase II study including all patients treated with whatever chemotherapy or combined modality regimen for whatever cancer who were in clinical objective response (complete response, CR, or partial response, PR) or stable disease (SD). The treatment consisted of administration of recombinant <em>interleukin</em>-2 (rIL-2) at a dose of 1.8 MIU subcutaneously three times/week (every other day) for the first 2 weeks of every month plus medroxyprogesterone acetate (MPA) 500 mg/day every other day plus antioxidant agents alpha-lipoic acid 300 mg/day and N-acetyl cysteine 1800 mg/day or carbocysteine lysine salt oral solution 2.7 g/day. The treatment was administered for 1 year except when progression of disease occurred. The primary study endpoints were to define clinical outcome, i.e. duration of response, survival (overall survival, OS and progression-free survival, PFS), the toxicity profile, and the evaluation of quality of life (QL). As secondary endpoints, we measured the changes of lymphocyte count, serum levels of proinflammatory cytokines, IL-2, C-reactive protein (CRP) and leptin, blood levels of reactive oxygen species (ROS) and antioxidant enzymes (glutathione peroxidase, GPx and superoxide dismertase, SOD). From July 1998 to June 2003, 42 patients were enrolled in the study (M/F ratio, 39/3; mean age, 62.5 years). Twenty (47.6%) patients were elderly >> 65 years). The majority of patients had either head and neck cancer or lung cancer, 88% had locally advanced or metastatic disease at diagnosis, and 76% had ECOG 0. Forty patients were previously treated with chemotherapy (<em>27</em> also with radiotherapy), two with IL-2 and interfiron (IFN), one with endocrine therapy and one with only surgery. We obtained an objective response to maintenance treatment of 50%. Median duration of response was 19 months and median PFS was 33 months. Median duration of maintenance treatment was 12 months, median follow-up duration from diagnosis to June 2003 was 40 months, and median follow-up duration from study entry to June 2003 was 17 months. The median overall survival has not been reached. Toxicity was negligible. As for QL, a significant improvement of cognitive functions was observed, whereas all other functioning and symptom scales did not change significantly. As for laboratory parameters, absolute lymphocyte count increased significantly, IL-6, IL-1 beta, tumor necrosis factor-alpha, CRP, and fibrinogen decreased significantly whereas IL-2 and leptin increased significantly after treatment. ROS decreased significantly, whereas GPx increased significantly after treatment. Patients alive at study end showed a significant increase in absolute lymphocyte count, IL-2, leptin, and GPx and a significant decrease of proinflammatory cytokines, CRP, fibrinogen, and ROS, whereas patients who died before study end exhibited only a significant increase in absolute lymphocyte count, IL-2, and GPx and a significant decrease of ROS. Long-term combined maintenance therapy with rIL-2 + MPA + antioxidant agents is feasible, has a very low toxicity, and results in the improvement of clinical outcome, QL, and laboratory parameters.

BACKGROUND

Overproduction of interleukin (IL)-6 may play a pathologic role in rheumatoid arthritis (RA) and chronic periodontitis (CP). The present study assesses IL-6 receptor (IL-6R) inhibition therapy on the periodontal condition of patients with RA and CP.

METHODS

The study participants were 28 patients with RA and CP during treatment with IL-6R inhibitor, and 27 patients with RA and CP during treatment without IL-6R inhibitor. Periodontal and rheumatologic parameters and serum levels of cytokine and inflammatory markers and immunoglobulin G against periodontopathic bacteria were examined after medication with IL-6R inhibitor for 20.3 months on average (T1) and again 8 weeks later (T2).

RESULTS

No differences were observed between the groups in any parameter values at T1, except for serum IL-6 levels. The anti-IL-6R group showed a significantly greater decrease in gingival index, bleeding on probing (BOP), probing depth (PD), clinical attachment level (CAL), and serum levels of IL-6 and matrix metalloproteinase (MMP)-3 from T1 to T2 than the control group (P <0.05). A significant correlation was found between changes in serum anticyclic citrullinated peptide levels and those in PD and CAL in the anti-IL-6R group (P <0.05), whereas both groups exhibited a significant association between changes in serum MMP-3 levels and those in BOP (P <0.05).

CONCLUSIONS

Changes in periodontal and serum parameter values were different between the patients with RA and CP during treatment with and without IL-6R inhibitor.

<em>Interleukin</em> (IL)-23 and IL-<em>27</em> have been recently identified as members of the IL-12 heterodimeric cytokine family. The cytokines are released from activated dentritic cells and play a crucial role in cell-mediated immunity. Expression profiles of the cytokines' receptors suggest that target cells of the cytokines are distinct depending on T cell maturation and differentiation. We first examined whether murine colon carcinoma cells (Colon 26) expressing IL-<em>27</em> (Colon 26/IL-<em>27</em>) could produce antitumor effects in syngeneic mice. The mice developed small Colon 26/IL-<em>27</em> tumors and subsequently rejected them, whereas parent tumors continued to grow. Since Colon 26/IL-12 and Colon 26/IL-23 cells were also rejected in syngeneic mice, we then investigated the combinatory antitumor effects of the cytokines. We inoculated Colon 26/IL-12, Colon 26/IL-23, Colon 26/IL-<em>27</em> cells or mixed populations of the cytokine producers into one flank of the mice that simultaneously received parent tumors in the other flank. The parent tumor growth influenced by the cytokine producers was similar to each other. Combinatory antitumor effects were not produced by the cytokine producers and application of the cytokines did not show any synergistic effects.