Interstitial granuloma after interferon-gamma and narrowband UVB therapy in a patient with mycosis fungoides: Immunological and histopathological considerations.

In mycosis fungoides (MF), cutaneous granuloma formation is unusual. Furthermore, MF showing interstitial granuloma, a rare type, after combination therapy with interferon-gamma (IFN-γ) and narrowband UVB (nbUVB) has not been previously reported. A 77-year-old man was referred to our hospital with a 2-month history of erythroderma. Biopsied specimens revealed infiltration of atypical lymphocytes and eosinophils. A diagnosis of an erythrodermic variant of MF was made. He was treated with combination therapy of IFN-γ and nbUVB. After the therapy, papules newly appeared and a histopathological specimen revealed interstitial granuloma. There were several CXCR3-positive cells around the granuloma. We speculated that the combination therapy made T-helper 1 cells migrate to the cutaneous lesion and resulted in the granuloma formation. Furthermore, judging from the disappearance of elastic fibers around the interstitial granuloma, we considered that IFN-γ may induce the infiltration of histiocytes interstitially after damage of elastic fibers caused by nbUVB therapy, and both IFN-γ and nbUVB may thus play an important role in the histogenesis. Not only histopathology but also immunological observations are needed to elucidate the mechanisms underlying the development of different types of granuloma in MF.

Cudraxanthone D Ameliorates Psoriasis-like Skin Inflammation in an Imiquimod-Induced Mouse Model via Inhibiting the Inflammatory Signaling Pathways.

Psoriasis is a chronic inflammatory skin disease accompanied by excessive keratinocyte proliferation. Corticosteroids, vitamin D3 analogs, and calcineurin inhibitors, which are used to treat psoriasis, have diverse adverse effects, whereas natural products are popular due to their high efficiency and relatively low toxicity. The roots of the Cudrania tricuspidata (C. tricuspidata) are known to have diverse pharmacological effects, among which the anti-inflammatory effect is reported as a potential therapeutic agent in skin cells. Nevertheless, its effectiveness against skin diseases, especially psoriasis, is not fully elucidated. Here, we investigated the effect of cudraxanthone D (CD), extracted from the roots the C. tricuspidata Bureau, on psoriasis using an imiquimod (IMQ)-induced mouse model and the tumor necrosis factor (TNF)-α/interferon (IFN)-γ-activated keratinocytes. IMQ was topically applied to the back skin of C57BL/6 mice for seven consecutive days, and the mice were orally administered with CD. This resulted in reduced psoriatic characteristics, such as the skin thickness and Psoriasis Area Severity Index score, and the infiltration of neutrophils in IMQ-induced skin. CD inhibited the serum levels of TNF-α, immunoglobulin G2a, and myeloperoxidase, and the expression of Th1/Th17 cells in splenocytes. In TNF-α/IFN-γ-activated keratinocytes, CD reduced the expressions of CCL17, IL-1ß, IL-6, and IL-8 by inhibiting the phosphorylation of STAT1 and the nuclear translocation of NF-kB. Taken together, these results suggest that CD could be a potential drug candidate for the treatment of psoriasis.

Interferon gamma induces inflammatory responses through the interaction of CEACAM1 and PI3K in airway epithelial cells.

BACKGROUND: Interferon gamma (IFNγ) plays an important role in the development of chronic lung diseases via the production of inflammatory mediators, although the exact mechanism remains unclear. The present study aimed at investigating the potential mechanisms by which IFNγ induced over-production of interleukins through the interaction between carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway. METHODS: IFN-γ induced over-production of interleukin (IL) 6 and IL8, and RNA expression of CEACAM1 and its subtypes or PI3K and its subtypes in human bronchial epithelial cells (HBE). The production of IL6 and IL8 or cell proliferation and movement were also evaluated in cellCEACAM1- or cellCEACAM1+ after the induction of IFN-γ. Roles of PI3K subtype proteins, e.g. PI3Kp110α/δ, Akt, p110α/γ/δ/ß/mTOR, PI3Kp110α/δ/ß, PI3Kp110δ, or pan-PI3K in IFN-γ-induced CEACAM1 subtype alterations were furthermore validated using those proteins of PI3K subtypes. RESULTS: CEACAM1, especially CEACAM1-S isoforms, was significantly up-regulated in HBE cells after treatment with IFN-γ. CEACAM1 played roles in expression of IL-6 and IL-8, and facilitated cellular proliferation and migration. IFN-γ up-regulated the expression of CEACAM1 in airway epithelial cells, especially CEACAM1-S isoforms, promoting cellular proliferation, migration, and the production of inflammatory factors. PI3K (p110δ)/Akt/mTOR pathway was involved in the process of IFN-γ-upregulated CEACAM1, especially CEACAM1-S. On the other hand, CEACAM1 could promote the activation of PI3K/Akt/mTOR pathway. CONCLUSION: IFN-γ could induce inflammatory responses, cellular growth and proliferation through the interaction of CEACAM1 (especially CEACAM1-S isoforms) and PI3K(p110δ)/Akt/mTOR in airway epithelial cells, which might be new alternative of future therapies against epithelial transition from inflammation to cancer.

GIFT-1, a phase IIa clinical trial to test the safety and efficacy of IFNγ administration in FRDA patients.

Friedreich's ataxia is an autosomal recessive progressive degenerative disorder caused by deficiency of the protein frataxin. The most common genetic cause is a homozygotic expansion of GAA triplets within intron 1 of the frataxin gene leading to impaired transcription. Preclinical in vivo and in vitro studies have shown that interferon gamma (IFNγ) is able to up-regulate the expression of frataxin gene in multiple cell types. We designed a phase IIa clinical trial, the first in Italy, aimed at assessing both safety and tolerability of IFNγ in Friedreich's patients and ability to increase frataxin levels in peripheral blood mononuclear cells. Nine patients (6 female and 3 males aged 21-38 years) with genetically confirmed disease were given 3 subcutaneous escalating doses (100, 150 and 200 µg) of IFNγ (human recombinant interferon 1 b gamma, trade name IMUKIN(®)), over 4 weeks. The primary end-point was the assessment of the safety and tolerability of IFNγ by means of standard clinical and hematological criteria. The secondary end-point was the detection of changes of frataxin levels in peripheral blood mononuclear cells after each single escalating dose of the drug. IFNγ was generally well tolerated, the main adverse event was hyperthermia/fever. Although, increases in frataxin levels could be detected in a minority of patients, these changes were not significant. A large phase III multicenter, randomized clinical trial with IFNγ in Friedreich's ataxia patients is currently ongoing. This study is expected to conclusively address the clinical efficacy of IFNγ therapy in patients with Friedreich's ataxia.

Inhibition of NADPH oxidase-1 preserves beta cell function.

AIMS/HYPOTHESIS: Upregulation of the reactive oxygen species (ROS)-producing enzyme NADPH oxidase (NOX)-1 in islets and beta cells follows acute exposure to inflammatory cytokines and is concomitant with beta cell dysfunction. NOX-1 is a candidate mediator of inflammation-induced beta cell dysfunction. This study aimed to determine whether selective inhibition of NADPH oxidase-1 presents a new strategy to preserve beta cell function. METHODS: Induced beta cell dysfunction was studied in primary human donor islets, isolated mouse islets and murine beta cell lines. Islets and beta cells were stimulated with inflammatory cytokines (TNF-α, IL-1ß, IFN-γ). NOX-1 activity was blocked by the selective inhibitor ML171. RESULTS: Cytokine induction of intracellular ROS was reduced 80% with 1 µmol/l ML171 in murine beta cell lines (p < 0.01). Cytokine-induced apoptosis, measured by caspase-3 activation or quantified fluorescence microscopy, was prevented in islets and beta cell lines up to 100% with ML171 in a concentration-dependent manner (p < 0.05). Functionally, glucose-stimulated insulin secretion was abolished by cytokine exposure but preserved by ML171 in isolated mouse islets and murine beta cell lines. A feed-forward regulation of NOX-1 in islets and beta cell lines was disrupted by ML171. CONCLUSIONS/INTERPRETATION: Stimulation of NOX-1 activity is a major component of inflammatory cytokine-induced beta cell dysfunction. Significant protection of beta cells is conferred with selective inhibition of NOX-1. Suppression of NOX-1 activity may present a new therapeutic strategy to preserve and protect beta cell function in diabetes.

Induction of tumor inhibitory anti-angiogenic response through immunization with interferon Gamma primed placental endothelial cells: ValloVax™.

BACKGROUND: While the concept of angiogenesis blockade as a therapeutic intervention for cancer has been repeatedly demonstrated, the full promise of this approach has yet to be realized. Specifically, drugs such as VEGF-blocking antibodies or kinase inhibitors suffer from the drawbacks of resistance development, as well as off-target toxicities. Previous studies have demonstrated feasibility of specifically inducing immunity towards tumor endothelium without consequences of systemic autoimmunity in both animal models and clinical settings. METHOD: Placenta-derived endothelial cells were isolated and pretreated with interferon gamma to enhance immunogenicity. Syngeneic mice received subcutaneous administration of B16 melanoma, 4 T1 mammary carcinoma, and Lewis Lung Carcinoma (LLC), followed by administration of control saline, control placental endothelial cells, and interferon gamma primed endothelial cells (ValloVax™). Tumor volume was quantified. An LLC metastasis model was also established and treated under similar conditions. Furthermore, a safety analysis in non-tumor bearing mice bracketing the proposed clinical dose was conducted. RESULTS: ValloVax™ immunization led to significant reduction of tumor growth and metastasis as compared to administration of non-treated placental endothelial cells. Mitotic inactivation by formalin fixation or irradiation preserved tumor inhibitory activity. Twenty-eight day evaluation of healthy male and female mice immunized with ValloVax™ resulted in no abnormalities or organ toxicities. CONCLUSION: Given the established rationale behind the potential therapeutic benefit of inhibiting tumor angiogenesis as a treatment for cancer, immunization against a variety of endothelial cell antigens may produce the best clinical response, enhancing efficacy and reducing the likelihood of the development of treatment resistance. These data support the clinical evaluation of irradiated ValloVax™ as an anti-angiogenic cancer vaccine.

Interferon-γ causes cardiac myocyte atrophy via selective degradation of myosin heavy chain in a model of chronic myocarditis.

Interferon-γ (IFN-γ), a proinflammatory cytokine, has been implicated in the pathogenesis of a number of forms of heart disease including myocarditis and congestive heart failure. In fact, overexpression of IFN-γ in mice causes dilated cardiomyopathy. However, the direct effects of IFN-γ on cardiac myocytes and the mechanism by which it causes cardiac dysfunction have not been described. Here, we present the molecular pathology of IFN-γ exposure and its effect on myofibrillar proteins in isolated neonatal rat ventricular myocytes. Treatment with IFN-γ caused cardiac myocyte atrophy attributable to a specific decrease in myosin heavy chain protein. This selective degradation of myosin heavy chain was not accompanied by a decrease in total protein synthesis or by an increase in total protein degradation. IFN-γ increased both proteasome and immunoproteasome activity in cardiac myocytes and their inhibition blocked myosin heavy chain loss and myocyte atrophy, whereas inhibition of the lysosome or autophagosome did not. Collectively, these results provide a mechanism by which IFN-γ causes cardiac pathology in the setting of chronic inflammatory diseases.

Interleukin-30: a novel antiinflammatory cytokine candidate for prevention and treatment of inflammatory cytokine-induced liver injury.

UNLABELLED: The liver is the major metabolic organ and is subjected to constant attacks from chronic viral infection, uptake of therapeutic drugs, life behavior (alcoholic), and environmental contaminants, all of which result in chronic inflammation, fibrosis, and, ultimately, cancer. Therefore, there is an urgent need to discover effective therapeutic agents for the prevention and treatment of liver injury, the ideal drug being a naturally occurring biological inhibitor. Here we establish the role of IL30 as a potent antiinflammatory cytokine that can inhibit inflammation-induced liver injury. In contrast, interleukin (IL)27, which contains IL30 as a subunit, is not hepatoprotective. Interestingly, IL30 is induced by the proinflammatory signal such as IL12 through interferon-gamma (IFN-γ)/signal transducer and activator of transcription 1 signaling. In animal models, administration of IL30 by way of a gene therapy approach prevents and treats both IL12-, IFN-γ-, and concanavalin A-induced liver toxicity. Likewise, immunohistochemistry analysis of human tissue samples revealed that IL30 is highly expressed in hepatocytes, yet barely expressed in inflammation-induced tissue such as fibrous/connective tissue. CONCLUSION: These novel observations reveal a novel role of IL30 as a therapeutic cytokine that suppresses proinflammatory cytokine-associated liver toxicity.

Withdrawing interferon-α from psychiatric patients: clinical care or unjustifiable stigma?

IFN-α is an effective therapy for chronic viral hepatitis C and today still represents an effective first-line treatment. Unfortunately, its use is associated with a number of side-effects, including psychiatric problems like depression, mania, psychosis, delirium and other cognitive disturbances. Clinicians have been concerned about the risks of worsening of pre-existent psychiatric disorders and of precipitating suicidal attempts in psychiatric patients. The presence of a mental illness is, therefore, often deemed to be a contraindication to the use of antiviral treatment. However, this amounts to stigmatization and discrimination, as it basically implies withholding a life-saving medical treatment because of a psychiatric diagnosis. Is this clinically and socially acceptable? With novel treatments now entering clinical practice as adjuvant to IFN-α, it is particularly important to make a statement now, to ensure that psychiatric patients are not left behind. The aim of this editorial is to critically discuss this notion, by reviewing the few studies (n = 14) that have indeed administered IFN-α to patients with a pre-existing psychiatric disorder. We find evidence that these patients have rates of treatment adherence and sustained virological response similar to those of non-psychiatric patients, and that their IFN-α-induced psychiatric symptoms respond successfully to clinical management. We conclude that there is no support to withdrawing IFN-α therapy from psychiatric patients.

IFN-γ promotes muscle damage in the mdx mouse model of Duchenne muscular dystrophy by suppressing M2 macrophage activation and inhibiting muscle cell proliferation.

Duchenne muscular dystrophy is a degenerative disorder that leads to death by the third decade of life. Previous investigations have shown that macrophages that invade dystrophic muscle are a heterogeneous population consisting of M1 and M2 macrophages that promote injury and repair, respectively. In the present investigation, we tested whether IFN-γ worsens the severity of mdx dystrophy by activating macrophages to a cytolytic M1 phenotype and by suppressing the activation of proregenerative macrophages to an M2 phenotype. IFN-γ is a strong inducer of the M1 phenotype and is elevated in mdx dystrophy. Contrary to our expectations, null mutation of IFN-γ caused no reduction of cytotoxicity of macrophages isolated from mdx muscle and did not reduce muscle fiber damage in vivo or improve gross motor function of mdx mice at the early, acute peak of pathology. In contrast, ablation of IFN-γ reduced muscle damage in vivo during the regenerative stage of the disease and increased activation of the M2 phenotype and improved motor function of mdx mice at that later stage of the disease. IFN-γ also inhibited muscle cell proliferation and differentiation in vitro, and IFN-γ mutation increased MyoD expression in mdx muscle in vivo, showing that IFN-γ can have direct effects on muscle cells that could impair repair. Taken together, the findings show that suppression of IFN-γ signaling in muscular dystrophy reduces muscle damage and improves motor performance by promoting the M2 macrophage phenotype and by direct actions on muscle cells.

Interferon-gamma with peginterferon alpha-2a and ribavirin in nonresponder patients with chronic hepatitis C (ANRS HC16 GAMMATRI).

BACKGROUND AND AIM: Interferon-gamma-1b (IFN-γ-1b) improves alpha interferon (IFN-α) inhibition of hepatitis C virus (HCV) replication in replicon system. We described virological response after addition of IFN-γ to a combination of ribavirin/peginterferon (PEG-IFN)-α-2a or α-2b. METHODS: In this non-comparative, multicenter trial, patients chronically infected by HCV who were nonresponders to a previous treatment by PEG-IFN and ribavirin were restarted on a regimen of PEG-IFN-α-2a (180 µg/week) + ribavirin (1000-1200 mg/day) for 16 weeks. If HCV-RNA decreased less than 2 log(10) copies/mL (nonresponders), and if PEG-IFN-α-2a and ribavirin dosages were unchanged while tolerance was good, IFNγ-1b (100 µg three times per week) was added for the last 32 weeks of treatment. Virological response was evaluated at week 28 (12 weeks after initiation of IFN-γ-1b). RESULTS: Among the 48 patients started on dual therapy, 23 patients (47%) were nonresponders at week 12 and received IFN-γ-1b from week 16 onward. Their mean HCV-RNA (log(10) IU/mL) was 6.83 at baseline, 5.81 at week 12, and 5.63 at week 28. No patient reached undetectable HCV-RNA at week 28 (upper bound of 95% confidence interval: 14.8%); none had a decrease > 1 log(10) IU/mL. One case of grade 4 neutropenia was reported. CONCLUSION: Among the strictly selected nonresponders, IFN-γ-1b (at a dosage of 100 µg thrice a week) in combination with PEG-IFN-α-2a and ribavirin failed to show virological efficacy.

Chemical composition and anti-inflammatory properties of the unsaponifiable fraction from awara (Astrocaryum vulgare M.) pulp oil in activated J774 macrophages and in a mice model of endotoxic shock.

Awara (Astrocaryum vulgare M.) pulp oil has been shown to possess anti-inflammatory properties in vivo, and contains an unsaponifiable matter rich in bioactive compounds. This study focused on the ethanolic unsaponifiable fraction (EUF) of awara pulp oil. Its chemical composition has been characterized: carotenoid, phytosterol, and tocopherol contents represent 125.7, 152.6, and 6.8 µg/mg of EUF, respectively. We further evaluated this fraction for anti-inflammatory properties in J774 macrophages activated by lipopolysaccharide (LPS) plus interferon (IFN) γ to understand the biological effects of awara pulp oil. EUF strongly decreased nitric oxide (NO), prostaglandin E(2), tumour necrosis factor (TNF) α, and interleukin (IL) -6 and -10 production in activated J774 cells. Moreover, it inhibited expression of inducible NO synthase and cyclooxygenases-2 in vitro. The anti-inflammatory properties of EUF were also confirmed in vivo by modulation of TNFα, IL-6 and IL-10 serum concentration in an endotoxic shock model. Pre-treatment with awara oil fraction offers promise as a protective means to lower the production of excessive amounts of pro-inflammatory molecules.

Predicting the risk for corneal graft rejection by aqueous humor analysis.

PURPOSE: Cytokine patterns determined in the aqueous humor before penetrating keratoplasty (PK) may enable us to predict immune reactions (IR). We therefore analyzed 6 cytokines in the aqueous humor of patients before PK. By prospective clinical follow-up, we tested whether patients who developed an IR would present different preoperative cytokine patterns compared to patients without IR. METHODS: We analyzed 18 samples of aqueous humor from 18 patients undergoing PK. The following cytokines were analyzed by cytometric bead array: interleukin 2 (IL-2), interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin 10 (IL-10), tumor-necrosis-factor α (TNF-α), and interferon γ (INF-γ). Seven patients presented with signs of IR during follow up. We performed Cox proportional hazards analysis to determine significant predictors for IR. We iteratively eliminated all co-variates with p values over 0.1 from the survival model (backward selection). RESULTS: Our final Cox model included the hazardous factors IL-4 (p=0.043) and INF-γ (p=0.059), protective factors IL-2 (p=0.081), IL-5 (p=0.028), and age at time of surgery (p=0.029). We performed a linear discriminant analysis based on these coefficients. The resulting function was: (-9.979*IL5) + (9.262*IL4) + (-3.928*IL2) + (1.709*IFN-γ) + (-0.183*age). A median of -4.97 separated patients with and without IR with no classification error. CONCLUSIONS: We demonstrate that cytokine levels in the aqueous humor can be predictive for IR. Our method allowed an almost 100% separation between patients with and without IR. This finding has the potential to improve the aftercare of PK fundamentally. However, our results need to be confirmed in a larger prospective cohort.

Treatment of disseminated mycobacterial infection with high-dose IFN-γ in a patient with IL-12Rß1 deficiency.

IFN-γ has been used in the treatment of IL-12Rß1 deficiency patients with disseminated BCG infection (BCGosis), but the optimal dose to reach efficacy is not clear. We used IFN-γ in the treatment of a 2.7-year-old patient with IL-12Rß1 deficiency and refractory BCG-osis. IFNγ was started at a dose of 50 µg/m² 3 times per week. The dose was upgraded to 100 mcg/m² after 3 months, then to 200 mcg/m² 6 months afterwards. Serum mycobactericidal activity and lymphocytes number and function were evaluated throughout the study. There was no clinical response to IFN-γ with 50 or 100 µg/m² doses. However, there was some response to the 200 µg/m² dose with no additional adverse effects. The serum mycobactericidal activity was not significantly different during the whole treatment period. Lymphocytes proliferation in response to PHA was significantly higher after 3 months of using the highest dose as compared to the lowest dose. The tuberculin skin test reaction remained persistently negative. We conclude that in a patient with IL-12Rß1 deficiency, IFN-γ at a dose of 200 µg/m², but not at lower dosages, was found to have a noticeable clinical effect with no additional adverse effects.

Tofacitinib overcomes an IFNγ-induced decrease in NK cell-mediated cytotoxicity via the regulation of immune-related molecules in LC-2/ad.

BACKGROUND: Immune checkpoint inhibitors targeting the programmed cell death-1 (PD-1)/PD-1 ligand 1 (PD-L1) axis have shown promising results in patients with nonsmall cell lung cancer (NSCLC). One major PD-L1 inducer is IFNγ, which is secreted by T cells and NK cells. Importantly, IFNγ-induced PD-L1 is one of the major mechanisms by which cancer cells escape host immunity. METHODS: Here, we found that the NSCLC cell line, LC-2/ad, has a unique character; the PD-L1 expression in these cells is up-regulated by both IFNγ and epidermal growth factor (EGF). RESULTS: Comparative analysis of the cell signaling pathway showed that IFNγ activates STAT1 signaling, while EGF activates AKT, MAPK, and ribosomal protein S6 kinase in LC-2/ad cells. IFNγ-induced PD-L1, but not EGF-induced PD-L1, was clearly blocked by the JAK-STAT inhibitor tofacitinib. Interestingly, IFNγ decreased the expression of NK cell-activating ligands while increasing the expression of MHC class I molecules, resulting in a phenotype that can easily escape from NK cells, theoretically. Finally, we showed that IFNγ stimuli attenuated NK cell-mediated cytotoxicity in LC-2/ad cells, which was, however, blocked by tofacitinib. CONCLUSIONS: Taken together, our study shows that tofacitinib blocks the IFNγ-induced transformation from an NK cell-sensitive phenotype to an NK cell-resistant one in IFNγ-reacted LC-2/ad cells, thereby implicating that tofacitinib may be a promising agent to overcome IFNγ-induced tumor immune escape, although it may be adapted to the limited number of NSCLC patients.

Exercise mimetics and JAK inhibition attenuate IFN-γ-induced wasting in engineered human skeletal muscle.

Chronic inflammatory diseases often lead to muscle wasting and contractile deficit. While exercise can have anti-inflammatory effects, the underlying mechanisms remain unclear. Here, we used an in vitro tissue-engineered model of human skeletal muscle ("myobundle") to study effects of exercise-mimetic electrical stimulation (E-stim) on interferon-γ (IFN-γ)-induced muscle weakness. Chronic IFN-γ treatment of myobundles derived from multiple donors induced myofiber atrophy and contractile loss. E-stim altered the myobundle secretome, induced myofiber hypertrophy, and attenuated the IFN-γ-induced myobundle wasting and weakness, in part by down-regulating JAK (Janus kinase)/STAT1 (signal transducer and activator of transcription 1) signaling pathway amplified by IFN-γ. JAK/STAT inhibitors fully prevented IFN-γ-induced myopathy, confirming the critical roles of STAT1 activation in proinflammatory action of IFN-γ. Our results reveal a previously unknown mechanism of the cell-autonomous anti-inflammatory effects of muscle exercise and establish the utility of human myobundle platform for studies of inflammatory muscle disease and therapy.

Comparing the protective effects of resveratrol, curcumin and sulforaphane against LPS/IFN-γ-mediated inflammation in doxorubicin-treated macrophages.

Doxorubicin (DOX) chemotherapy is associated with the release of inflammatory cytokines from macrophages. This has been suggested to be, in part, due to DOX-mediated leakage of endotoxins from gut microflora, which activate Toll-like receptor 4 (TLR4) signaling in macrophages, causing severe inflammation. However, the direct function of DOX on macrophages is still unknown. In the present study, we tested the hypothesis that DOX alone is incapable of stimulating inflammatory response in macrophages. Then, we compared the anti-inflammatory effects of curcumin (CUR), resveratrol (RES) and sulforaphane (SFN) against lipopolysaccharide/interferon-gamma (LPS/IFN-γ)-mediated inflammation in the absence or presence of DOX. For this purpose, RAW 264.7 cells were stimulated with LPS/IFN-γ (10 ng/mL/10 U/mL) in the absence or presence of DOX (0.1 µM). Our results showed that DOX alone is incapable of stimulating an inflammatory response in RAW 264.7 macrophages. Furthermore, after 24 h of incubation with LPS/IFN-γ, a significant increase in tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and inducible nitric oxide synthase (iNOS) mRNA levels was observed. Similarly, nitric oxide (NO) production and TNF-α and IL-6 protein levels were significantly upregulated. Moreover, in LPS/IFN-γ-treated macrophages, the microRNAs (miRNAs) miR-146a, miR-155, and miR-21 were significantly overexpressed. Interestingly, upon testing CUR, RES, and SFN against LPS/IFN-γ-mediated inflammation, only SFN was able to significantly reverse the LPS/IFN-γ-mediated induction of iNOS, TNF-α and IL-6 and attenuate miR-146a and miR-155 levels. In conclusion, SFN, at the transcriptional and posttranscriptional levels, exhibits potent immunomodulatory action against LPS/IFN-γ-stimulated macrophages, which may indicate SFN as a potential treatment for DOX-associated inflammation.

Recombinant gamma interferon induces hypertriglyceridemia and inhibits post-heparin lipase activity in cancer patients.

Animals suffering from malignancy or chronic infection develop characteristic metabolic abnormalities, including a well-defined hypertriglyceridemic state. These abnormalities have been attributed to release of one or more mediators from activated macrophages. We report that cancer patients receiving RIFN-gamma, a potent macrophage activator, at doses of greater than or equal to 0.25 mg/m2/d i.m. show marked increases in triglyceride but not in cholesterol levels (pretreatment triglyceride level of 180 +/- 190 mg/dl [mean +/- SD] vs. a day-14 level of 370 +/- 242 mg/dl, n = 23, p less than 0.001 by the paired t test). This hypertriglyceridemia was characterized by an increase in very low-density lipoproteins and a decrease in plasma post-heparin lipase activity, consistent with defective triglyceride clearance (mean pretreatment lipase level of 2.1 mumol/ml/h vs. a day-14 level of 1.2 mumol/ml/h, n = 6, p = 0.02 by the paired t test). rIFN-gamma did not directly inhibit lipoprotein lipase enzymatic activity in vitro. Other possible mechanisms of action, such as suppression of lipase by an rIFN-gamma-induced mediator released from activated macrophages, or a direct effect of interferon on lipase biosynthesis, require further investigation. Our observations provide evidence that factors produced by the immune system can regulate lipid metabolism in man.

Prolonged treatment with recombinant interferon gamma induces erythema nodosum leprosum in lepromatous leprosy patients.

10 patients with borderline and lepromatous leprosy were selected for a prolonged trial with recombinant interferon gamma (rIFN-gamma). Patients received 30 micrograms intradermally for six injections over a 9-d period, and then either 100 micrograms intradermally every 1 mo for 10 mo or every 2 wk for 5 mo (total, 1.2 mg). Erythema nodosum leprosum (ENL) was induced in 60% of the patients within 6-7 mo, as compared with an incidence of 15% per year with multiple drug therapy alone. The mean whole-body reduction in bacterial index over the first 6 mo was 0.9 log units. Cutaneous induration at the intradermal injection sites of greater than or equal to 15 mm predicted the development of a subsequent reactional state. Monocytes obtained from patients receiving the lymphokine demonstrated an increased respiratory burst and a 2.5-5.1-fold increase in tumor necrosis factor alpha (TNF-alpha) secretion in response to agonists. Patients in ENL had an even higher release of TNF-alpha from monocytes as well as high levels of TNF-alpha in the plasma (mean, 2,000 pg/ml). Thalidomide therapy was required to treat the systemic manifestations of ENL. Control of toxic symptoms with thalidomide was associated with a 50-80% reduction in agonist-stimulated monocyte TNF-alpha secretion. IFN-gamma enhanced the monocyte release of TNF-alpha by 3-7.5-fold (agonist dependent) when added to patient's cells in vitro, and this could be suppressed by the in vitro addition of 10 micrograms/ml of thalidomide.

Quality of life in patients with advanced renal cell carcinoma treated with temsirolimus or interferon-alpha.

BACKGROUND: Temsirolimus was approved in Europe as first-line treatment of poor-prognosis advanced renal cell carcinoma (advRCC) based on significant clinical benefits. METHODS: Patients with advRCC and multiple poor-prognostic factors were randomly assigned to receive 25 mg intravenous temsirolimus weekly, interferon-alpha (titrated to 18 mU) three times weekly, or 15 mg intravenous temsirolimus weekly plus 6 mU of interferon-alpha three times weekly. EuroQol-5D utility score (EQ-5D index) and the EQ-5D visual analogue scale (EQ-VAS) responses were recorded. For analysis, patients were required to have their EQ-5D data recorded at baseline, week 12, and last visit after week 12. The analysis was conducted using last-visit data and a repeated-measures mixed-effect (RMME) model to evaluate quality-of-life differences between temsirolimus and interferon-alpha, controlling for baseline covariates. RESULTS: Average EQ-5D score at the last measure was significantly higher in patients receiving temsirolimus compared with interferon-alpha: by 0.10 on EQ-5D index (P=0.0279) and by 6.61 on EQ-VAS (P=0.0095). In the RMME model, the least-square mean for on-treatment EQ-5D index score was 0.590 with temsirolimus and 0.492 with interferon-alpha (P=0.0022). CONCLUSION: Temsirolimus is associated with significantly higher EQ-5D scores compared with interferon-alpha in patients with previously untreated poor-prognosis advRCC.