BACKGROUND

Psychosocial factors are associated with the development and progress of cardiovascular disease, but the pathological mechanisms remain unclear. We examined the associations of psychosocial risk factors for cardiovascular disease with concentrations of inflammatory markers among healthy adults and assessed the extent to which these associations are mediated by behaviors, body mass index (BMI), and diabetes mellitus.

METHODS

This cross-sectional study used data from the baseline examination of the Multi-Ethnic Study of Atherosclerosis, a multisite study of 6814 men and women aged 45 to 84 years. Regression analyses were used to estimate associations of cynical distrust, chronic stress, and depression with serum levels of C-reactive protein, IL-6, and fibrinogen before and after adjustment for socioeconomic position, behaviors, BMI, and diabetes.

RESULTS

Higher levels of cynical distrust were associated with higher levels of inflammatory markers. The percentage differences (95% confidence intervals [CIs]) comparing the 80th and 20th percentiles of the scale were 7% (3%-11%) for IL-6; 9% (2%-16%) for C-reactive protein; and 1.3% (0.1%-2.4%) for fibrinogen. Higher levels of chronic stress were associated with higher concentrations of IL-6 and C-reactive protein. The percentage differences (95% CIs) comparing 2 and 0 ongoing stressful circumstances were 4% (1%-8%) for IL-6 and 5% (1%-11%) for C-reactive protein. Depression was positively associated with the level of IL-6 (percentage difference [95% CI] comparing the Center for Epidemiologic Studies-Depression Scale scores of>>or=21 vs <21 was 7% [1%-14%]). Associations of psychosocial factors with inflammatory markers were reduced by 20% to 55% after adjustment for behavioral factors and by 45% to 100% after adjustment for BMI and diabetes, mostly owing to the effect of BMI. No associations remained after controlling for socioeconomic position, behaviors, BMI, and diabetes.

CONCLUSIONS

Psychosocial factors are associated with higher levels of inflammatory markers, most consistently for cynical distrust. Results are compatible with a mediating role of BMI, behaviors, and diabetes.

Toll-like receptors (TLRs) expressed on immune cells trigger inflammatory responses. TLRs are also expressed on ovarian cancer (OvCa) cells, but the consequences of signaling by the TLR4/MyD88 pathway in these cells are unclear. Here, TLR4 and MyD88 expression in OvCa tissues (n=<em>20</em>) and cell lines (OVCAR3, SKOV3, AD10, A2780 and CP70) was evaluated by reverse transcriptase-PCR, western blots and immunohistochemistry. Cell growth, apoptosis, nuclear factor-kappaB (NF-kappaB) translocation, IRAK4 and TRIF expression and cJun phosphorylation were measured following tumor cell exposure to the TLR4 ligands, lipopolysaccharide (LPS) or paclitaxel (PTX). Culture supernatants were tested for cytokine levels. TLR4 was expressed in all tumors, tumor cell lines and normal epithelium. MyD88 was detectable in tumor tissues and in 3/5 OvCa lines but not in normal cells. In MyD88(+) SCOV3 cells, LPS or PTX binding to TLR4 induced IRAK4 activation and cJun phosphorylation, activated the NF-kappaB pathway and promoted interleukin (<em>IL</em>)-8, <em>IL</em>-6, vascular endothelial growth factor and monocyte chemotactic protein-1 production and resistance to drug-induced apoptosis. Silencing of TLR4 in SCOV3 cells with small interference RNA resulted in phosphorylated-cJun (p-cJun) downregulation and a loss of PTX resistance. In PTX-sensitive, MyD88(neg) A2780 cells, TLR4 stimulation upregulated TRIF, and TLR4 silencing eliminated this effect. Thus, TLR4/MyD88 signaling supports OvCa progression and chemoresistance, promoting immune escape.

Airway mucus is a hallmark of respiratory syncytial virus (RSV) lower respiratory tract illness. Laboratory RSV strains differentially induce airway mucus production in mice. Here, we tested the hypothesis that RSV strains differ in pathogenesis by screening six low-passage RSV clinical isolates for mucogenicity and virulence in BALB/cJ mice. The RSV clinical isolates induced variable disease severity, lung interleukin-13 (<em>IL</em>-13) levels, and gob-5 levels in BALB/cJ mice. We chose two of these clinical isolates for further study. Infection of BALB/cJ mice with RSV A<em>20</em>01/2-<em>20</em> (2-<em>20</em>) resulted in greater disease severity, higher lung <em>IL</em>-13 levels, and higher lung gob-5 levels than infection with RSV strains A2, line 19, Long, and A<em>20</em>01/3-12 (3-12). Like the line 19 RSV strain, the 2-<em>20</em> clinical isolate induced airway mucin expression in BALB/cJ mice. The 2-<em>20</em> and 3-12 RSV clinical isolates had higher lung viral loads than laboratory RSV strains at 1 day postinfection (p.i.). This increased viral load correlated with higher viral antigen levels in the bronchiolar epithelium and greater histopathologic changes at 1 day p.i. The A2 RSV strain had the highest peak viral load at day 4 p.i. RSV 2-<em>20</em> infection caused epithelial desquamation, bronchiolitis, airway hyperresponsiveness, and increased breathing effort in BALB/cJ mice. We found that RSV clinical isolates induce variable pathogenesis in mice, and we established a mouse model of clinical isolate strain-dependent RSV pathogenesis that recapitulates key features of RSV disease.

The unique immunological properties of the liver may be due to the function of hepatic dendritic cells (DC). However, liver DC have not been well characterized because of the difficulty in isolating adequate numbers of cells for analysis. Using immunomagnetic bead and flow cytometric cell sorting, we compared freshly isolated murine liver and spleen CD11c+ DC. We found that liver DC are less mature, capture less Ag, and induce less T cell stimulation than spleen DC. Nevertheless, liver DC were able to generate high levels of <em>IL</em>-12 in response to CpG stimulation. We identified four distinct subtypes of liver DC based on the widely used DC subset markers CD8alpha and CD11b. Lymphoid (CD8alpha+CD11b-) and myeloid (CD8alpha-CD11b+) liver DC activated T cells to a similar degree as did their splenic DC counterparts but comprised only <em>20</em>% of all liver DC. In contrast, the two more prevalent liver DC subsets were only weakly immunostimulatory. Plasmacytoid DC (B2<em>20</em>+) accounted for 19% of liver DC, but only 5% of spleen DC. Our findings support the widely held notion that liver DC are generally weak activators of immunity, although they are capable of producing inflammatory cytokines, and certain subtypes potently activate T cells.

BACKGROUND

Interleukin (IL)-32 is a newly described proinflammatory cytokine that seems likely to play a role in inflammation and host defense. Little is known about the regulation of IL-32 production by primary cells of the immune system.

RESULTS

In the present study, freshly obtained human peripheral blood mononuclear cells were stimulated with different Toll-like receptor (TLR) agonists, and gene expression and synthesis of IL-32 was determined. We demonstrate that the TLR4 agonist lipopolysaccharide induces moderate (4-fold) production of IL-32, whereas agonists of TLR2, TLR3, TLR5, or TLR9, each of which strongly induced tumor necrosis factor alpha and IL-6, did not stimulate IL-32 production. However, the greatest amount of IL-32 was induced by the mycobacteria Mycobacterium tuberculosis and M. bovis BCG (20-fold over unstimulated cells). IL-32-induced synthesis by either lipopolysaccharide or mycobacteria remains entirely cell-associated in monocytes; moreover, steady-state mRNA levels are present in unstimulated monocytes without translation into IL-32 protein, similar to other cytokines lacking a signal peptide. IL-32 production induced by M. tuberculosis is dependent on endogenous interferon-gamma (IFNgamma); endogenous IFNgamma is, in turn, dependent on M. tuberculosis-induced IL-18 via caspase-1.

CONCLUSIONS

In conclusion, IL-32 is a cell-associated proinflammatory cytokine, which is specifically stimulated by mycobacteria through a caspase-1- and IL-18-dependent production of IFNgamma.

We investigated inflammatory and physiologic parameters in sepsis models of increasing lethality induced by cecal ligation and puncture (CLP). Mice received imipenem for antibiotic therapy, and groups were sacrificed at 2, 4, 8, 12, 16, <em>20</em>, and 24 h after CLP. The severity of sepsis increased with needle puncture size (lethality with 18-gauge puncture [18G], 100%; 21G, 50%; 25G, 5%; sham treatment, 0%). While the temperature (at 12 h) and the activity and diurnal rhythm (at day 4) of the 25G-treated CLP group recovered to normal, the 21G and 18G treatment groups exhibited severe hypothermia along with decreased activities. A direct correlation was also observed between the severity of sepsis and cytokine (interleukin 1beta [<em>IL</em>-1beta], tumor necrosis factor [TNF], <em>IL</em>-6, and <em>IL</em>-10) concentrations in both the peritoneum and the plasma. There were substantially higher cytokine levels in the more severe CLP models than in the sham-treated one. Peritoneal and plasma TNF levels were always less than 40 pg/ml in all models. None of the cytokines in the septic mice peaked within the first hour, which is in contrast to the results of most endotoxin models. Chemokine (KC and macrophage inflammatory protein 2) profiles also correlated with the severity of sepsis. Except for the chemokines, levels of inflammatory mediators were always higher at the site of inflammation (peritoneum) than in the circulation. Our study demonstrated that sepsis of increasing severity induced increased cytokine levels both within the local environment (peritoneum) and systemically (plasma), which in turn correlated with morbidity and mortality.

BACKGROUND

Currently available immunosuppressive regimens for cadaver-kidney recipients are far from ideal because acute-rejection episodes occur in about 30% to 50% of these patients. In the phase III study described here we assessed the ability of basiliximab, a chimeric interleukin (IL)-2 receptor monoclonal antibody, to prevent acute-rejection episodes in renal allograft recipients.

METHODS

380 adult recipients of a primary cadaveric kidney transplant were randomly allocated, in this double-blind trial, to receive a 20 mg infusion of basiliximab on day 0 (day of surgery) and on day 4, to provide IL-2-receptor suppression for 4-6 weeks (n=193), or to receive placebo (n=187). Both groups received baseline dual immunosuppressive therapy with cyclosporin and steroids throughout the study. The primary outcome measure was incidence of acute-rejection episodes during the 6 months after transplantation. Safety and tolerability were monitored over the 12 months of the study.

RESULTS

376 patients were eligible for intention-to-treat analysis (basiliximab, n=190; placebo, n=186). No significant differences in patient characteristics were apparent. The incidence of biopsy-confirmed acute rejection 6 months after transplantation was 51 (29.8%) of 171 in the basiliximab group compared with 73 (44.0%) of 166 in the placebo group (32% reduction; 14.2% difference [95% Kaplan-Meier CIs 3% to 24%], p=0.012). The incidence of steroid-resistant first rejection episodes that required antibody therapy was significantly lower in the basiliximab group (10% vs 23.1%, 13.1% difference [5.4% to 20.8%], p<0.001). At weeks 2 and 4 post-transplantation, the mean daily dose of steroids was significantly higher in the placebo group (p<0.001 with one-way analysis of variance). The incidence of graft loss at 12 months post-transplantation was 23 (12.1%) of 190 in the basiliximab group and 25 (13.4%) of 186 in the placebo group (1.3% difference [-5% to 9%], p=0.591). The incidence of infection and other adverse events was similar in the two treatment groups. The acute tolerability of basiliximab was excellent, with no evidence of cytokine-release syndrome. 14 deaths (basiliximab n=9; placebo n=5; -2.0% difference [-6% to 2%], p=0.293) occurred during the 12-month study and a further three deaths (basiliximab n=1; placebo n=2) occurred within the 380-day cut-off period. One post-transplantation lymphoproliferative disorder was recorded in each group.

CONCLUSIONS

Prophylaxis with 40 mg basiliximab reduces the incidence of acute rejection episodes significantly, with no clinically relevant safety or tolerability concerns.

Exuberant tumor-like synovial cell proliferation with invasion of periarticular bone is a feature of rheumatoid arthritis in humans and of streptococcal cell wall (SCW)-induced arthritis in rats. These histologic observations prompted us to examine synoviocytes from arthritic joints for phenotypic characteristics of transformed cells. The capacity to grow in vitro under anchorage-independent conditions is a characteristic that correlates closely with potential in vivo tumorigenicity. In medium supplemented with <em>20</em>% serum or in basal media supplemented with platelet-derived growth factor (PDGF), early passage synoviocytes from both SCW-induced and rheumatoid arthritic joints formed colonies in soft agarose. Epidermal growth factor (EGF), interleukin 1 (<em>IL</em>-1), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and transforming growth factor-beta (TGF-beta) did not support growth, although EGF enhanced PDGF-dependent growth. On the other hand, TGF-beta, as well as all-trans-retinoic acid, inhibited colony growth. Early passage normal rat and human synoviocytes also grew under the same conditions, but lung, skin, and late-gestation embryonic fibroblast-like cells did not. Considered in the context of other published data our findings provide cogent evidence that synoviocytes, but not other types of fibroblast-like cells, readily acquire phenotypic characteristics commonly associated with transformed cells. Expression of the transformed phenotype in the inflammatory site is likely regulated by paracrine growth factors, such as PDGF and TGF-beta.

Sleep disturbance is associated with inflammation and related disorders including cardiovascular disease, arthritis, and diabetes mellitus. Given sex differences in the prevalence of inflammatory disorders with stronger associations in females, this study was undertaken to test the effects of sleep loss on cellular mechanisms that contribute to proinflammatory cytokine activity. In 26 healthy adults (11 females; 15 males), monocyte intracellular proinflammatory cytokine production was repeatedly assessed at 08:00, 12:00, 16:00, <em>20</em>:00, and 23:00h during a baseline period and after partial sleep deprivation (awake from 23:00 to 3.00h). In the morning after a night of sleep loss, monocyte production of interleukin-6 (<em>IL</em>-6) and tumor necrosis factor-alpha (TNF-alpha) differentially changed between the two sexes. Whereas both females and males showed a marked increase in the lipopolysaccharide (LPS) - stimulated production of <em>IL</em>-6 and TNF-alpha in the morning immediately after PSD, production of these cytokines during the early- and late evening was increased in the females as compared to decreases in the males. Sleep loss induces a functional alteration of monocyte proinflammatory cytokine responses with females showing greater cellular immune activation as compared to changes in males. These results have implications for understanding the role of sleep disturbance in the differential risk profile for inflammatory disorders between the sexes.

Alterations in the immune system may have importance for the pathophysiology of depression. Several studies have linked increased production of pro-inflammatory cytokines to depression and depressive symptoms. There is growing evidence that antidepressive treatment may influence the production of pro-and anti-inflammatory cytokines. In the present study we aimed to find associations between the levels of soluble interleukin-2 receptor (s<em>IL</em>-2R), interleukin-8 (<em>IL</em>-8) and tumor necrosis factor alpha (TNF-alpha) and the response to antidepressant treatment in patients with major depression. Our study group consisted of 100 patients (35 males and 65 females) who were treated with escitalopram 10-<em>20</em> mg/day for 12 weeks. Responders and non-responders were identified according to Montgomery-Asberg's Depression Rating Scale (MADRS) scores. The levels of cytokines were measured at baseline and at 4th and 12th week of the treatment and compared to cytokine concentrations in healthy volunteers (n=45; 19 males and 26 females). Our data indicated that a higher level of TNF-alpha might predict a non-response to treatment with escitalopram and that changes in concentrations of s<em>IL</em>-2R during the treatment were different in responders and non-responders.

OBJECTIVE

Depressive symptomatology is frequently associated with interleukin (IL)-2 and interferon alfa-2b (INFalpha-2b) therapy in cancer patients. The objective of the present study was to evaluate the depressive and anxiety symptoms induced by IL-2 and/or INFalpha-2b in cancer patients during the first days of cytokine immunotherapy.

METHODS

The study included 48 patients with renal cell carcinoma or melanoma. Patients were treated either with subcutaneous IL-2, alone (n = 20) or in combination with INFalpha-2b (n = 6); or with INFalpha-2b alone, administered subcutaneously at a low dose (n = 8) or intravenously at a high dose (n = 14). Depressive symptoms were evaluated using the Montgomery and Asberg Depression Rating Scale (MADRS), and anxiety symptoms were evaluated using the Covi scale. Evaluations were performed just before initiation of treatment (day 1) and on days 3 and 5 of treatment.

RESULTS

Patients treated with IL-2 alone or in association with INFalpha-2b had significantly higher MADRS scores after 5 days of cytokine therapy, and patients who received both cytokines had increased scores on day 3. In contrast, patients treated with INFalpha-2b alone did not have varying MADRS scores during the course of treatment. Cytokine therapy had no effect on anxiety, except in patients treated with IL-2 in combination with INFalpha-2b. In these patients, the enhancement in anxiety scores that was observed on day 5 was mainly attributable to increased somatic complaints.

CONCLUSIONS

IL-2 and INFalpha-2b have differential effects on mood, and IL-2 therapy induces depressive symptoms early in treatment.

Angiogenesis is an ordered process requiring the inter-play of numerous cellular and humoral factors. Studies over the past <em>20</em> years have identified several growth factors, cytokines, and enzymes that promote blood vessel formation. Most have revealed how individual factors promote an angiogenic phenotype in endothelial cells in vitro or contribute to blood vessel formation in vivo. However, the fundamental question that remains unanswered is how the cellular microenvironment contributes to angiogenesis. Fibrocytes are a recently characterized mesenchymal cell type isolated from peripheral blood that rapidly enter subcutaneously implanted wound chambers and sites of tissue injury. Here we describe the induction of an angiogenic phenotype in microvascular endothelial cells in vitro and promotion of angiogenesis in vivo by cultured fibrocytes. Fibrocytes constitutively secrete extracellular matrix-degrading enzymes, primarily matrix metalloproteinase 9, which promotes endothelial cell invasion. In addition, fibrocytes secrete several proangiogenic factors including VEGF, bFGF, <em>IL</em>-8, PDGF, and hematopoietic growth factors that promote endothelial cell migration, proliferation, and/or tube formation. By contrast, they do not produce representative antiangiogenic factors. Finally, both autologous fibrocytes and fibrocyte-conditioned media were found to induce blood vessel formation in vivo using the Matrigel angiogenesis model.

The purpose of the current study was to test the hypothesis that an altered fat distribution in elderly healthy subjects and in patients with type-2 diabetes contributes to high circulating levels of interleukin (<em>IL</em>)-6 and tumor necrotic factor (TNF)-alpha, which secondly is related to lower muscle mass. Twenty young controls, (<em>20</em>-35 yr), <em>20</em> healthy elderly subjects (65-80 yr) and 16 elderly patients with type 2 diabetes (65-80 yr) were included in a cross sectional study. Plasma levels of TNF-alpha and <em>IL</em>-6 were measured after an overnight fast. Dual-energy X-ray absorptiometry and total body potassium counting measured truncal fat, appendicular skeletal muscle mass (ASM) and body cell mass (BCM), respectively. TNF-alpha, <em>IL</em>-6 and the relative truncal fat mass were higher in elderly compared with young controls. ASM was lower in diabetic men than in young controls and BCM was lower in elderly men compared with young men. TNF-alpha and <em>IL</em>-6 were correlated with the absolute as well as the relative truncal fat mass in univariate regression analyses. Similar results were found in multivariate linear regression analyses after adjusting for the effect of age and gender. TNF-alpha was related to lower ASM and BCM in elderly men both in a univariate regression analysis and a multivariate regression analysis. In conclusion, high plasma levels of TNF-alpha and <em>IL</em>-6 in elderly healthy people and in patients with type 2 diabetes are associated with increased truncal fat mass, suggesting that cytokines are partly derived from this adipose tissue bed. Furthermore, TNF-alpha was related to lower ASM and BCM, suggesting that TNF-alpha contributes to sarcopenia in ageing.

The role for <em>IL</em>-10 in the immunopathogenesis of acute toxoplasmosis following peroral infection was examined in both genetically susceptible C57BL/6 and resistant BALB/c mice. C57BL/6-background <em>IL</em>-10-targeted mutant (<em>IL</em>-10-/-) mice all died in 2 wk after infection with <em>20</em> cysts of the ME49 strain, whereas only <em>20</em>% of control mice succumbed. Histological studies revealed necrosis in the small and large intestines and livers of infected <em>IL</em>-10-/- mice. The necrosis in the small intestine was the most severe pathologic response and was not observed in control mice. Treatment of infected <em>IL</em>-10-/- mice with either anti-CD4 or anti-IFN-gamma mAb prevented intestinal pathology and significantly prolonged time to death. Treatment of these animals with anti-<em>IL</em>-12 mAb also prevented the pathology. Significantly greater amounts of IFN-gamma mRNA were detected in the lamina propria lymphocytes obtained from the small intestine of infected <em>IL</em>-10-/- mice than those from infected control mice. In common with C57BL/6-background <em>IL</em>-10-/- mice, BALB/c-background <em>IL</em>-10-/- mice all died developing intestinal pathology after infection. Control BALB/c mice all survived even after infection with 100 cysts and did not develop the intestinal lesions. Treatment with anti-IFN-gamma mAb prevented the pathology and prolonged time to death of the infected <em>IL</em>-10-/- mice. These results strongly suggest that <em>IL</em>-10 plays a critical role in down-regulating IFN-gamma production in the small intestine following sublethal peroral infection with Toxoplasma gondii and that this down-regulatory effect of <em>IL</em>-10 is required for prevention of development of IFN-gamma-mediated intestinal pathology and mortality in both genetically resistant BALB/c and susceptible C57BL/6 mice.

beta 2-IFN/hepatocyte stimulating factor/<em>IL</em>-6 is a cytokine secreted by monocytes, fibroblasts, and endothelial cells in cell culture that possesses diverse biologic activity including the stimulation of acute phase plasma protein synthesis and immunomodulation. The circulating levels of this cytokine in man in response to bacterial LPS (endotoxin) were studied. A single i.v. bolus of endotoxin (<em>20</em> U/kg) produced a monophasic rise in circulating immunoreactive IFN-beta 2/<em>IL</em>-6 and IFN-beta 2/<em>IL</em>-6 bioactivity (hepatocyte stimulation and B cell differentiation assays) peaking 2 to 4 h after the endotoxin challenge. Peak IFN-beta 2/<em>IL</em>-6 levels ranged from 4.1 to 27.5 ng/ml. Associated with this was a rise in circulating C-reactive protein levels detected <em>20</em> h after the endotoxin bolus. Thus, IFN-beta 2/<em>IL</em>-6 is likely one of the endogenous mediators which is triggered in man during bacterial infection and likely participates in the metabolic and immune responses of the infected host.

OBJECTIVE

To compare the concentrations of cytokines belonging to Th17 axis (interleukin (IL)-17 and IL-23) and Th1 axis (IL-12 and interferon (IFN)-gamma) in obese and lean women, and to investigate their relationships with the proinflammatory adipokine leptin, proinflammatory cytokine macrophage migration inhibitory factor (MIF) and anthropometric and metabolic parameters of obesity.

METHODS

Cross-sectional study.

METHODS

Twenty-six obese women (age 20-52 years, body mass index (BMI): 30-48 kg/m(2)) and 20 healthy lean women (age 23-46 years, BMI: 18-25 kg/m(2)).

METHODS

Plasma levels of cytokines and leptin, BMI, waist circumference (WC) and insulin resistance index HOMA (homeostatic model assessment).

RESULTS

Blood concentrations of IL-17, IL-23, MIF and leptin, but not IL-12 or IFN-gamma, were higher in obese compared with lean women (P=0.002, 0.046, 0.006 and 0.002, respectively). There was a positive correlation between IL-17 and IL-23 (r(s)=0.530), which was at the border of statistical significance (P=0.065). Neither IL-17 nor IL-23 correlated with leptin or MIF, and there was no association between IL-17 and IL-23 levels with BMI, WC or HOMA index.

CONCLUSIONS

Interleukin-23/IL-17 axis is stimulated in obese women independently of the increase in abdominal fat, insulin resistance, leptin and MIF levels.

BACKGROUND

It is well established that glutamine supplemented elemental diets result in less severe intestinal damage in experimental colitis. However, few studies have examined the mode of action of glutamine in reducing intestinal damage.

OBJECTIVE

To examine the effects of glutamine supplemented elemental diets on the potent inflammatory cytokines interleukin 8 (IL-8) and tumour necrosis factor alpha (TNF-alpha) in trinitrobenzene sulphonic acid (TNBS) induced colitis which presents with both acute and chronic features of ulcerative colitis.

METHODS

Sprague-Dawley rats were randomised into three dietary groups and fed 20% casein (controls), or 20% casein supplemented with either 2% glutamine (2% Gln) or 4% glutamine (4% Gln). After two weeks they received intracolonic TNBS to induce colitis.

RESULTS

Both Gln groups of rats gained more weight than the control group (p < 0.05) which had progressive weight loss. Colon weight, macroscopic, and microscopic damage scores for the Gln groups were lower than in the control group (p < 0.05). IL-8 and TNF-alpha concentrations in inflamed colonic tissues were lower in the Gln groups than in the control group (p < 0.05), and correlated well with disease severity. Bacterial translocation was lower both in incidence (p < 0.05) and in the number of colony forming units (p < 0.05) for the Gln groups, than in the control group. With respect to all indices studied, the 4% Gln group performed better than did the 2% Gln group.

CONCLUSIONS

Prophylactic glutamine supplementation modulates the inflammatory activities of IL-8 and TNF-alpha in TNBS induced colitis.

BACKGROUND

Flu-like symptoms are common, early transient side effects of paclitaxel chemotherapy. We hypothesized that these symptoms may be due to release of inflammatory cytokines in response to treatment. The objective of this study was to assess changes in plasma levels of interleukin (IL)-1beta, IL-6, IL-8, IL-10, IL-12, and TNF-alpha during chemotherapy and to correlate these changes with musculoskeletal symptoms.

METHODS

Ninety patients with breast cancer were included; 70 patients received single agent paclitaxel either weekly or every 3 weeks and 20 received FAC (5-FU, doxorubicin, cyclophosphamide) chemotherapy. Fifteen healthy volunteers were included as controls. Cytokines and symptoms were measured before starting therapy, on day 3 and on the last day of one treatment cycle.

RESULTS

At baseline, all subjects had measurable levels of IL-8 but only 49% had IL-12, 45% had IL-10, 32% had IL-6, and 21% had IL-1beta or TNF-alpha in their plasma. There was no difference in baseline cytokine levels between cancer patients and the healthy volunteers. Schedule-dependent transient changes in the levels of 3 cytokines were observed in the paclitaxel treated patients. In the every 3-week paclitaxel group, IL-6 and IL-8 increased whereas in the weekly paclitaxel group IL-10 increased significantly compared to baseline. Fatigue and flu-like symptoms were also worse on day 3. In the weekly paclitaxel group, increase in IL-10 level correlated positively with joint pain (p=0.003). In the every 3-week paclitaxel group, increase in IL-8 level correlated positively with flu-like symptom (p=0.008). In the FAC-treated group and among the healthy volunteers none of these cytokines increased significantly.

CONCLUSIONS

Weekly paclitaxel induces transient increase in IL-10 levels whereas every 3-week higher dose treatments induce IL-8 and IL-6 in the plasma. These changes correlate with joint pain and flu-like symptoms.

OBJECTIVE

Severe obesity is a chronic inflammatory disease where various cytokines/adipocytokines play a key role. Pro-inflammatory cytokines such as interleukin 6 (IL-6) and tumour necrosis factor-alpha (TNFalpha) are produced by human adipose tissue dependent on the degree of obesity. Mouse studies suggest a key role of adipose tissue-derived IL-6 in hepatic insulin resistance via modification of liver suppressor of cytokine signalling 3 (SOCS-3) expression.

METHODS

We examined the effect of excessive weight loss on systemic levels, subcutaneous and visceral adipose tissue and liver expression of IL-6 and TNFalpha in 20 severely obese patients undergoing laparoscopic adjustable gastric banding (LAGB). Furthermore, we studied liver expression of SOCS3, an important regulator of insulin resistance, and fat tissue expression of the anti-inflammatory adipocytokine adiponectin and its receptors. Serum and tissue samples were collected before and 6 months after LAGB surgery.

RESULTS

IL-6/TNFalpha mRNA expression before weight loss were similar in subcutaneous and visceral adipose tissue and much higher compared to hepatic expression. Subcutaneous adipose tissue mRNA expression of both pro-inflammatory cytokines, but especially of IL-6 decreased dramatically after extensive weight loss whereas expression of adiponectin and its receptors increased. Weight loss also led to a significant reduction in liver IL-6 expression, whereas liver TNFalpha mRNA expression did not change. IL-6 and C-reactive protein serum levels decreased after weight loss whereas TNFalpha serum levels were below the detection limit before and after surgery. These effects were paralleled by reduced hepatic SOCS3 expression and improved insulin resistance 6 months after LAGB surgery.

CONCLUSIONS

Expression of IL-6 and TNFalpha mRNA is more pronounced in adipose compared to liver tissue in patients with severe obesity. Our results highlight excessive weight loss as a successful anti-inflammatory strategy.

Parkinson's disease is characterized by a progressive degeneration of substantia nigra (SN) dopaminergic neurons with age. We previously found that a single systemic lipopolysaccharide (LPS, 5 mg/kg, i.p.) injection caused a slow progressive loss of tyrosine hydroxylase immunoreactive (TH+IR) neurons in SN associated with increasing motor dysfunction. In this study, we investigated the role of NADPH oxidase (NOX) in inflammation-mediated SN neurotoxicity. A comparison of control (NOX2(+/+) ) mice with NOX subunit gp91(phox) -deficient (NOX2(-/-) ) mice 10 months after LPS administration (5 mg/kg, i.p.) resulted in a 39% (P < 0.01) loss of TH+IR neurons in NOX2(+/+) mice, whereas NOX2(-/-) mice did not show a significant decrease. Microglia (Iba1+IR) showed morphological activation in NOX2(+/+) mice, but not in NOX2(-/-) mice at 1 hr. Treatment of NOX2(+/+) mice with LPS resulted in a 12-fold increase in NOX2 mRNA in midbrain and 5.5-6.5-fold increases in NOX2 protein (+IR) in SN compared with the saline controls. Brain reactive oxygen species (ROS), determined using diphenyliodonium histochemistry, was increased by LPS in SN between 1 hr and <em>20</em> months. Diphenyliodonium (DPI), an NOX inhibitor, blocked LPS-induced activation of microglia and production of ROS, TNFα, <em>IL</em>-1β, and MCP-1. Although LPS increased microglial activation and ROS at all ages studied, saline control NOX2(+/+) mice showed age-related increases in microglial activation, NOX, and ROS levels at 12 and 22 months of age. Together, these results suggest that NOX contributes to persistent microglial activation, ROS production, and dopaminergic neurodegeneration that persist and continue to increase with age.

American women have a nearly 25% lifetime risk of developing breast cancer, with <em>20</em>% to 40% of these patients developing life-threatening metastases. More than 70% of patients presenting with metastases have skeletal involvement, which signals progression to an incurable stage. Tumor-stroma cell interactions are only superficially understood, specifically regarding the ability of stromal cells to affect metastasis. In vivo models show that exogenously supplied human bone marrow-derived stem cells (hBMSC) migrate to breast cancer tumors, but no reports have shown endogenous hBMSC migration from the bone to primary tumors. Here, we present a model of in vivo hBMSC migration from a physiologic human bone environment to human breast tumors. Furthermore, hBMSCs alter tumor growth and bone metastasis frequency. These may home to certain breast tumors based on tumor-derived TGF-β1. Moreover, at the primary tumor level, interleukin 17B (<em>IL</em>-17B)/<em>IL</em>-17BR signaling may mediate interactions between hBMSCs and breast cancer cells.

OBJECTIVE

Regulatory T cells play a major role in tumor escape from immunosurveillance. T regulatory cells type 1 (Tr1), a subset of regulatory T cells present in the tumor and peripheral circulation of patients with head and neck squamous cell carcinoma (HNSCC), mediate immune suppression and might contribute to tumor progression.

METHODS

CD4+CD25-T cells were isolated from peripheral blood mononuclear cells (PBMC) or tumor-infiltrating lymphocytes (T<em>IL</em>) of 26 HNSCC patients and 10 normal controls. The Tr1 cell phenotype was determined before and after culture in the presence of interleukin (<em>IL</em>)-2, <em>IL</em>-10, and <em>IL</em>-15, each at 10 to <em>20</em> IU/mL. Suppression was measured in carboxyfluorescein diacetate succinimidyl ester-based proliferation assays with or without neutralizing anti-<em>IL</em>-10 or anti-transforming growth factor-beta1 (TGF-beta1) monoclonal antibodies in Transwell systems. ELISA was used to define the Tr1 cytokine profile.

RESULTS

Tr1 cells originate from CD4(+)CD25(-) precursors present in TIL and PBMC of HNSCC patients. Cytokine-driven ex vivo expansion of Tr1 precursors yielded CD4+CD25-Foxp3lowCD132+IL-10+TGF-beta1+ populations that mediated higher suppression than Tr1 cells of normal controls (P < 0.0001). Tr1 cells suppressed proliferation of autologous responders via IL-10 and TGF-beta1 secretion. Expression of these cytokines was higher in TIL-derived than PBMC-derived Tr1 cells (P < 0.0001). The Tr1 cell frequency and suppressor function were significantly higher in patients presenting with advanced than early disease stages and in patients "cured" by oncologic therapies than in those with active disease.

CONCLUSIONS

In HNSCC, Tr1 cell generation is promoted at the tumor site. Tr1 cells use TGF-beta and IL-10 to mediate suppression. They expand during disease progression and also following cancer therapy in patients with no evident disease.

Many survivors of breast cancer show significant cognitive impairments, including memory deficits. Inflammation induced by chemotherapy may contribute to hippocampal changes that underlie these deficits. In this cross-sectional study, we measured bilateral hippocampal volumes from high-resolution magnetic resonance images in 42 chemotherapy-treated breast cancer survivors and 35 healthy female controls. Patients with breast cancer were, on average, 4.8 ± 3.4 years off-therapy. In a subset of these participants (<em>20</em> breast cancer, 23 controls), we quantified serum cytokine levels. Left hippocampal volumes and memory performance were significantly reduced and interleukin-6 (<em>IL</em>-6) and tumor necrosis factor-alpha (TNFα) concentrations were significantly elevated in the breast cancer group compared to controls. In the breast cancer group, lower left hippocampal volume was associated with higher levels of TNFα and lower levels of <em>IL</em>-6 with a significant interaction between these two cytokines suggesting a potential modulatory effect of <em>IL</em>-6 on TNFα. Verbal memory performance was associated with cytokine levels and left hippocampal volume in both groups. These findings provide evidence of altered hippocampal volume and verbal memory difficulties following breast cancer chemotherapy that may be mediated by TNFα and <em>IL</em>-6.

This systematic review sets out to give a comprehensive overview of the cytokine profile at the onset of psychosis un-confounded by medication. We aim to provide insight into the early pathophysiological process of psychosis and areas for future research of potential biomarkers able to chart the extent of illness or effectiveness of treatment. Following PRISMA guidelines, a systematic primary search identified 4638 citations, 4651 studies were retrieved and screened, and 23 studies met the inclusion criteria (published in English before June <em>20</em>13, patients with neuroleptic naive first episode psychosis, and assessed circulating cytokines). These reported 570 patients, 683 healthy control subjects, and <em>20</em> cytokine/cytokine receptors. Papers that contained sufficient stratified data were included in a random-effects pooled effect size meta-analysis. Highly significant effect sizes were found for elevated <em>IL</em>-1β, s<em>IL</em>-2r, <em>IL</em>-6, and TNF-α. Non-significant effect size estimates were obtained for <em>IL</em>-2, <em>IL</em>-4, and IFN-γ. Thus, we found significant elevation in pro-inflammatory cytokine levels in the serum of patients with medication-naive first episode psychosis. This adds to the evidence of a pro-inflammatory immune deregulation in schizophrenia and suggests these cytokines should be the focus for further research in biomarkers of progress and extent of illness. Future studies should focus on the medication-naive group at the early stages of illness with numbers large enough to allow for the control of other potential confounding factors.