Genotoxicity Evaluation of the Soybean Isoflavone Genistein in Human Papillary Thyroid Cancer Cells. Study of Its Potential Use in Thyroid Cancer Therapy.

Genistein is one of the several known isoflavonic phytoestrogens found in a number of plants, with soybeans and soy products being the primary food source. The aim of the study is to evaluate if genistein is able to exert antineoplastic action in primary human papillary thyroid cancer (PTC) cells. Thyroid tissues were treated with genistein (1-10-50-100 µM). Cell viability, proliferation, DNA primary damage and chromosomal damage were evaluated. An antiproliferative effect was induced by the highest doses of genistein, and such an effect was synergistically enhanced by the cotreatment with the antineoplastic drug sorafenib. Comet assay did not show any genotoxic effect in terms of primary DNA damage at all the times (4 and 24 h) and tested doses. A reduction of hydrogen peroxide-induced DNA primary damage in primary thyrocytes from PTC cells pretreated with genistein was observed. Data suggest that genistein exerts antineoplastic action, does not induce genotoxic effects while reduces oxidative-induced DNA damage in primary thyrocytes from PTC cells, supporting its possible use in therapeutic intervention.

CXCL8 and CXCL11 chemokine secretion in dermal fibroblasts is differentially modulated by vanadium pentoxide.

An increase in skin rashes or atopic dermatitis has been observed in individuals working with vanadium. However, to the best of our knowledge no in vivo or in vitro studies have evaluated the effect of exposure to vanadium in dermal fibroblasts. Cells viability and proliferation were assessed by WST­1 assay, cells were treated with increasing concentrations of V2O5 (1, 10 and 100 nM). CXCL8 and CXCL11 concentrations were measured in the supernatants using an ELISA assay. V2O5 was not observed as having a significant effect on dermal fibroblast's viability and proliferation. However, it was revealed that V2O5 was able to induce the secretion of CXCL8 and CXCL11 chemokines into dermal fibroblasts. V2O5 synergistically increased the effect of interferon (IFN)γ on CXCL11 secretion. In addition, V2O5 synergistically increased the effect of the tumor necrosis factor α on CXCL8 secretion and abolished the inhibitory effect of IFNγ. V2O5 induction of CXCL8 and CXCL11 chemokines may lead to the appearance and perpetuation of an inflammatory reaction into the dermal tissue. Further studies are required to evaluate dermal integrity and manifestations in subjects occupationally exposed, or living in polluted areas.

Induction of Th1 chemokine secretion in dermal fibroblasts by vanadium pentoxide.

Vanadium is a soft, silvery­grey metal with a number of different oxidation states. The most common commercial form of vanadium is vanadium pentoxide (V2O5). All vanadium compounds are considered toxic. An increase in skin rashes has been observed in certain vanadium workers, including the development of atopic dermatitis. However, to the best of our knowledge, no prior in vivo or in vitro studies have evaluated the effect of vanadium exposure in human dermal fibroblasts. The present study evaluated the effect of V2O5 on proliferation and chemokine secretion in dermal fibroblasts. The results revealed that V2O5 had no significant effect on the viability or proliferation of fibroblasts, however it was able to induce the secretion of T­helper (Th)1 chemokines from dermal fibroblasts, synergistically increasing the effect of important Th1 cytokines, including interferon­Î³ and tumor necrosis factor­α. Through these processes, V2O5 may lead to the induction and perpetuation of an inflammatory reaction in dermal tissue. The induction and perpetuation of inflammation in the dermis and the variety of involved candidate genes may be at the base of V2O5­induced effects following occupational and environmental exposures. Further studies are necessary to evaluate dermal integrity and manifestations in subjects who are occupationally exposed, or living in polluted areas.

Vanadium pentoxide induces the secretion of CXCL9 and CXCL10 chemokines in thyroid cells.

Vanadium is a grey metal, existing in different states of oxidation, whose most common form in commercial products is vanadium pentoxide (V2O5). All vanadium compounds have been considered toxic. A carcinogenic role of vanadium on the thyroid has recently been proposed. However no in vivo or in vitro studies have evaluated thyroid disruption in humans and/or animals after exposure to vanadium. In the present study we evaluate the effect of V2O5 on proliferation, and chemokine secretion in normal thyrocytes. Our study demonstrated that V2O5 has no effect on thyroid follicular cell viability or proliferation, but it is able to induce the secretion of T-helper (Th)1 chemokines into the thyroid, synergistically increasing the effect of important Th1 cytokines such as interferon (IFN)γ and tumor necrosis factor (TNF)α. Through this process, V2O5 promotes the induction and perpetuation of an inflammatory reaction in the thyroid. Further studies are necessary to evaluate thyroid function, and nodules, in subjects occupationally exposed, or living in polluted areas.

High risk of brain tumors in military personnel: a case control study.

Scientific literature suggests a relationship between military occupation and the development of brain tumors, but no italian study has investigated on the impact of this job on the brain cancer morbidity. In this a study information were obtained from patients recruited in the Neurosurgical Department of the University-Hospital of Pisa, Italy, from 1990 to 1999. The study has been conducted as a case-control study. 161, newly diagnosed cases of brain tumors (glioma and meningiomas, histologically confirmed), were recruited, such as 483 controls (with other non tumoral neurologic diseases: trauma, hemorrhagic brain disorders, aneurism, etc), by matching cases and controls (1:3), for age (± 5 years) and gender. Cases and controls were interviewed in the Neurosurgical Department, University-Hospital of Pisa, Italy, and the occupational histories of cases and controls were compared. Cases and controls have showed a statistically significant difference, based on their occupation (military vs. non-military occupation). A statistically significant association was seen between brain tumors and military occupation among evaluated patients (p=0.013). Further studies regarding this population group are needed, to determine the causes for the increased risk of this cancer. Furthermore, a subsequent reevaluation in other patients collected in more recent years will be needed to evaluate the trend of this association.

High risk of brain tumors in farmers: a mini-review of the literature, and report of the results of a case control study.

Even though a relationship between farmer work and the development of brain tumors was suggest by the scientific literature, a small number of italian studies investigate on the impact of this job on the cancer morbidity of farmer population. The informations about this case-control study were obtained from patients recruited in the Neurosurgical Department of the University-Hospital of Pisa, Italy, from 1990 to 2000. One hundred and seventy-four, newly diagnosed cases of brain tumors (glioma and meningiomas, histologically confirmed), were recruited, such as 522 controls (with other non tumoral neurologic diseases: trauma, etc), by matching cases and controls (1:3), for age (± 5 years) and gender. Cases and controls were interviewed in the Neurosurgical Department, University-Hospital of Pisa, Italy, and the occupational histories of cases and controls were compared. Cases and controls have showed a statistically significant difference, based on their occupation (agricultural vs. non-agricultural). We observed a significant association among brain tumors and rural activity in evaluated patients (P=0.008). Further studies regarding this population group are needed, to determine the causes for the increased risk of this cancer, particularly in regions where there is an intense agricultural activity and where pesticides are used. Furthermore, a subsequent reevaluation in other patients collected in more recent years will be needed to evaluate the trend of this association.

Both 3,5-diiodo-L-thyronine (T2) and T3 modulate glucose-induced insulin secretion.

3,5-diiodo-L-thyronine (T2), a naturally existing iodothyronine, has biological effects on humans, but no information is available on its action on pancreatic b-cells. We evaluated its effect vs triiodothyronine (T3), on glucose-induced insulin secretion in INS-1e cells, a rat insulinoma line, and on human islets. INS-1e were incubated in the presence/absence of T2 or T3 (0.1 nmol/L-10 µmol/L), and glucose (3.3, 7.5, 11.0, and 20 mmol/L). Insulin release and content (at 11.0 and 20 mmol/L glucose) were significantly (p less than 0.01) stimulated by 1-100 nmol/L T2 and 0.1 nmol/L-1.0 µmol/L T3, and inhibited with higher concentrations of both (1–10 µmol/L T2 and 10 µmol/L T3). Human islets were incubated with 3.3 mmol/L glucose in presence/absence of T3 or T2 (0.1 nmol/L, 0.1 µmol/L, and 1 µmol/L). T2 (0.1 nmol/L-0.1 µmol/L) significantly (p less than0.01) stimulated insulin secretion, while higher concentrations (1 µmol/L) inhibited it. A modest increase in insulin secretion was evidenced with 1 µmol/L T3. In conclusion, T2 and T3 have a direct regulatory role in insulin secretion, depending on their concentrations and the glucose level itself. At concentrations near the physiological range, T2 enhances glucose-induced insulin secretion in both rat b-cells and human islets.

Favorable effects of myo-inositol, selenomethionine or their combination on the hydrogen peroxide-induced oxidative stress of peripheral mononuclear cells from patients with Hashimoto's thyroiditis: preliminary in vitro studies.

OBJECTIVE: The aim of this study was to assess whether blood mononuclear cells (PBMC) from Hashimoto's thyroiditis (HT) and control women, were protected from in vitro H2O2-induced oxidative stress after addition of antioxidants. PATIENTS AND METHODS: PBMC, from 8 HT women and 3 healthy women (controls), were cultured in the presence of 200 µM H2O2 alone, with subsequent addition of myo-inositol (Myo) (0.25, 0.5, 1.0 µM), selenomethionine (SelMet) (0.25, 0.5, 1.0 µM), or their combination (0.25+0.25, 0.5+0.5, 1.0+1.0 µM). PBMC proliferation, vitality, genotoxicity (Comet score) and secretion in the medium of the chemokines CXCL10 [IP10], CCL2 e CXCL9 [MIG] were the indices measured. RESULTS: PBMC proliferation was decreased by H2O2 alone, and it decreased further and dose-dependently in either group (greatest decrease with Myo+SelMet in HT). H2O2 alone decreased vitality by 5% in controls and 10% in the HT group, but vitality was rescued by the three additions. The addition of H2O2 alone increased the Comet score at +505% above baseline in controls and +707% in HT women. In either group, each addition dose-dependently contrasted genotoxicity. Concentrations of chemokines in the medium were increased by H2O2 alone, and in HT women more than in controls. Each addition dose-dependently decreased these concentrations in either group, and often below baseline levels, with Myo+SelMet being the most potent addition (up to approximately -80% of baseline). CONCLUSIONS: The tested antioxidants exert beneficial effects on PBMC exposed in vitro to H2O2-induced oxidative stress in both control and HT women. Particularly, the association Myo+SelMet is the most effective. After the demonstration of a favorable in vitro outcomes in a large cohort of HT patients, we could predict favorable in vivo outcomes given by the same supplement. Thus, one can select HT patients with a high chance of benefit from supplementation.

Myo-inositol and selenium reduce the risk of developing overt hypothyroidism in patients with autoimmune thyroiditis.

OBJECTIVE: The beneficial effects obtained by myo-inositol in association with seleno-methionine in patients affected by subclinical hypothyroidism have been recently demonstrated. Here, we evaluate the immune-modulating effect of myo-inositol in association with seleno-methionine in patients with euthyroid autoimmune thyroiditis (AT). PATIENTS AND METHODS: Twenty-one consecutive Caucasian patients with newly diagnosed euthyroid chronic AT were evaluated. All subjects were treated with myo-inositol in association with selenium (600 mg/83 mg) tablets, twice per day, for six months. A complete thyroid assessment was done before the treatment, and after six months. RESULTS: After the treatment thyroid-stimulating hormone (TSH) levels significantly declined with respect to basal values, overall in patients with an initial TSH value in the high normal range (2.1

Bladder cancer and Th1 chemokines

Bladder cancer arises from the epithelial lining of the urinary bladder, and it is known as transitional cell carcinoma (TCC). Tobacco smoking is the main known contributor to urinary bladder cancer. However thirty percent of bladder tumors probably result from occupational exposure in the workplace to carcinogens. Immunotherapy by intravesicular delivery of Bacillus Calmette­Guérin (BCG) is used to treat and prevent the recurrence of superficial bladder cancer. Successful BCG immunotherapy for bladder cancer is associated with proper induction of T helper (Th)1 immunity. In bladder cancer patients after intravesicular BCG, urine was found to contain high levels of IP-10, and Interferon (IFN)-γ. TCC and endothelial cell lines were able to secrete IP-10 in response to BCG or IFN stimulation in vitro. Furthermore intravesicular BCG induces a cytokine-rich urinary microenvironment that is inhibitory to human endothelial cells and it is anti-angiogenetic by the induction of Th1 chemokines. Other studies suggest that therapeutic strategies involving Th1 induction and Th2 dampening may improve responses to immunotherapy. Further studies are needed to evaluate the IP-10 in circulation, and urine, as prognostic marker of bladder cancer patients, also in relation to BCG immunotherapy

Hypersensitivity pneumonitis and alpha-chemokines.

Hypersensitivity pneumonitis (HP) is categorized as a Type-1 helper (Th1) disease. The resulting granuloma formation is dependent on T cells and the Th1 cytokine interferon (IFN)-γ. In experimental setting, the production of IFN-γ-induced protein 10 (IP-10), monokine induced by IFN-γ (MIG), IFN-inducible T-cell-alpha chemoattractant (I-TAC), has been shown (in mice exposed to the particulate antigens that cause HP) during the development of HP. The production of these chemokines was associated with an influx of chemokine (C-X-C motif) receptor (CXCR)3 CXCR3(+)/CD4(+) T cells into lungs. This suggests that IFN-γ mediates the recruitment of CXCR3(+)/CD4(+) T cells into the lung via the production of IP-10, MIG, and I-TAC, resulting in granuloma formation. In humans it has been shown that lymphocytes infiltrating lung biopsies are CD8 T cells for CXCR3. Furthermore, the T cells accumulating in the bronchoalveolar lavage (BAL) of HP were CXCR3(+)/IFN-γ(+) type 1 CD8(+) T cells (Tc1) exhibiting a strong in vitro migratory capability in response to IP-10. Alveolar macrophages express and secrete, in response to IFN-γ, high levels of IP-10, capable of inducing chemotaxis of the CXCR3(+) T-cell line. High levels of CXCR3 ligands were shown in the fluid of the BAL in HP patients. These data confirm that IFN-γ mediates the recruitment of lymphocytes into the lung via production of IP-10, resulting in Tc1-cell alveolitis and granuloma formation. It has been suggested that differences in the expression of CXC chemokines and Th1 cytokines may contribute to different immunopathogenesis, clinical course and responsiveness to treatment of HP.

Interferon-γ-induced protein 10 in Lyme disease.

Lyme disease is an infectious disease caused by bacteria of the Borrelia type, that affects about 300,000 people a year in the USA and 65,000 people a year in Europe. Borrelia infection, and Lyme disease, following occupational exposure has been frequently reported in USA, Europe and Asia. The manifestations of Lyme disease include erythema migrans (EM), arthritis, neuroborrelliosis (NB), and others. Cytokines and chemokines primarily orchestrate leukocyte recruitment to the areas of Borrelia infection, and they are critical mediators of immune and inflammatory responses, in particular of the induction of interferon (IFN)-γ and IFN-γ dependent chemokines. In EM high levels of T helper (Th) 1 cells chemoattranctants [monokine induced by IFN-γ (MIG), IFN-γ-induced protein 10 (IP- 10), and IFN-inducible T cell alpha chemoattractant (I-TAC)] have been shown. Synovial tissues and fluids of patients with Lyme Arthritis (LA) (overall with antibiotic-refractory LA) contained exceptionally high levels of Th1 chemoattractants and cytokines, particularly MIG and IFN-γ. In NB concentrations of IP-10 and I-TAC in the cerebrospinal fluid (CSF) were significantly higher, suggesting that IP-10 and I-TAC create a chemokine gradient between the CSF and serum and recruite C-X-C chemokine receptor 3-expressing memory CD4+ T-cells into the CSF of these patients. A positive association between the disseminating capacity of B. burgdorferi and early type I IFN induction has also been shown. These results suggest that IFN-γ dependent chemokines are important biomarkers to monitor the progression and diffusion of the disease in patients with Borrelia infection; further larger studies are needed.

IP-10 in occupational asthma: review of the literature and case-control study.

OBJECTIVES: T-helper (Th)2 cytokines are thought to mediate most of the allergic inflammatory responses associated with atopic asthma. But the Th1-related chemokine, interferon (IFN)-γ-induced protein 10 (IP-10)/chemokine (C-X-C motif) ligand (CXCL)10, was the predominant chemokine measured during human allergic pulmonary late-phase reaction. Viral infection and allergens can exacerbate asthma by inducing the accumulation of these chemokines and inflammatory cells in the airway. Short-acting ß2-adrenoreceptor agonists, budesonide and formoterol (all important relievers in asthma exacerbation), such as vitamin D3, vitamin C, have been shown to inhibit airway cells inflammatory responses by modulating these chemokines. Furthemore it has been suggested that Th1-related IP-10 and monokine induced by IFN-γ (MIG)/CXCL9 may be useful inflammatory markers of asthma exacerbation. PATIENTS AND METHODS: In this study we have evaluated serum levels of the Th1-related CXC chemokine IP-10, in 8 patients with occupational asthma (OA) during exacerbation due to occupational exposure, and after 2-3 months, when patients were in stable conditions, in comparison with 8 age and gender matched healthy subjects. RESULTS: A significant increase in the serum levels of IP-10 were found in OA patients with an acute exacerbation in contrast to healthy controls (p<0.01), and in comparison with same OA patients after 2-3 months, when they were without any respiratory symptoms or disorders. CONCLUSIONS: These results suggest that the Th1-related CXC chemokines IP-10 is an useful inflammatory marker of OA exacerbation. However, other studies in larger number of patients are needed.

Hepatocellular carcinoma and CXCR3 chemokines: a narrative review.

Hepatocellular carcinoma (HCC) results from several factors like viral hepatitis infection [hepatitis B, or C (25%)] or occupational exposure. T-helper (Th)1 inflammatory cells, characterized by interferon (IFN)-γ and interleukin (IL)-2 secretion, predominate in the liver during chronic HCV infection, and chemokines attracting these cells are particularly important in disease progression. Among C-X-C chemokines, the non-ELR group [as IFN-γ-induced protein 10 (IP-10), monokine induced by IFN-γ (MIG) and IFN-inducible T-cell-alpha chemoattractant (I-TAC)], attracts Th1-cells interacting with chemokine C-X-C receptor (CXCR3). IP-10 has uniquely been shown to have prognostic utility as a marker of treatment outcome. IFN- γ-induced chemokines, as MIG and IP-10, may promote lymphocyte recruitment to HCC playing important roles in cancer immunology. The production of CXC chemokines by HCC cell lines has been shown. It has been identified immune-gene signature that predicts patient survival including the chemokine gene IP-10. Inflammatory cytokines (tumour necrosis factor-α, IFN-γ) and Toll-like receptor 3 ligands stimulate intratumoral production of these chemokines which drive T and Natural Killer cells tumor infiltration, leading to enhanced cancer cell death. Furthermore selective recruitment of CXCR3(+) B-cells that bridges proinflammatory IL-17 response and protumorigenic macrophage polarization in HCC has been shown, suggesting that blocking CXCR3(+) B-cell migration or function may help defeat HCC. It has been also shown that the overexpression of IP-10, which induced by liver graft injury, may lead to cisplatin resistance via ATF6/Grp78 ER stress signaling pathway in HCC; IP-10 neutralizing antibody could be a potential adjuvant therapy to sensitize HCC-cisplatin treatment.

Allergic rhinitis and CXCR3 chemokines.

The underlying mechanism of allergic rhinitis involves IgE antibodies attaching to the allergen and causing the release of inflammatory chemicals such as histamine from mast cells. Cytokines are very important in this process. Many data suggest a systemic shift to more intensely type 1-dominated immune responses in non-allergic individuals and, conversely, to more type 2-dominated responses in allergic individuals upon natural re-exposure to grass pollen. However other studies have found that chemokine (C-X-C motif) ligand (CXCL)10/ interferon (IFN)-γ-induced protein 10 (IP-10) and CXCL9/monokine induced by IFN-γ (MIG) concentrations are elevated in nasal lavages from allergic patients suggesting that these chemokines may play a role in chronic allergic inflammation. Several studies have also evaluated the effect of different immune-modulating drugs in allergic rhinitis showing local and peripheral increase of IFN-γ and IP-10, associated with a reduction of symptoms. Further studies are needed to clarify the role of T helper (Th)1 chemokines in the pathogenesis of allergic rhinitis, and to evaluate their role as biomarkers of disease and of response to treatments.

Serum 25-OH vitamin D levels in systemic sclerosis: analysis of 140 patients and review of the literature.

Hypovitaminosis D is increasingly reported in autoimmune diseases. We investigated the 25-OH-vitamin D (25-OH-vitD) levels in systemic sclerosis (SSc) patients, in correlation with disease's features. We measured the 25-OH-vitD serum levels in 140 consecutive patients (F/M 126/15; mean age 61 ± 15.1 years), 91 without (group A) and 49 with (group B) 25-OH-cholecalciferol supplementation. Patients of group A invariably showed low 25-OH-vitD levels (9.8 ± 4.1 ng/ml vs. 26 ± 8.1 ng/ml of group B); in particular, 88/91 (97%) patients showed vitamin D deficiency (<20 ng/ml), with very low vitamin D levels (<10 ng/ml) in 40 (44%) subjects. Only 15/49 (30.6%) patients of group B reached normal levels of 25-OH-vitD (≥30 ng/ml), whereas vitamin D deficiency persisted in 12/49 (24.5%) individuals. Parathormone levels inversely correlated with 25-OH-vitD (r = -0.3, p < 0.0001). Of interest, hypovitaminosis D was statistically associated with autoimmune thyroiditis (p = 0.008), while calcinosis was more frequently observed in patients of group A (p = 0.057). Moreover, we found significantly higher percentage of serum anticentromere antibodies in group B patients with 25-OH-vitD level ≥30 ng/ml (8/15 vs. 6/34; p = 0.017). In literature, hypovitaminosis D is very frequent in SSc patients. An association with disease duration, calcinosis, or severity of pulmonary involvement was occasionally recognized. Hypovitaminosis D is very frequent in SSc and severe in a relevant percentage of patients; furthermore, less than one third of supplemented subjects reached normal levels of 25-OH-vitD. The evaluation of 25-OH-vitD levels should be included in the routine clinical work-up of SSc. The above findings expand previous observations and may stimulate further investigations.

Leishmaniasis and IFN-γ dependent chemokines.

Leishmaniasis is a disease caused by Leishmania and spread by the bite of certain types of sandflies. Leishmaniasis affects as many as 12 million people worldwide, with 2 million new cases each year. Leishmania infection, and Leishmaniasis, following occupational exposure has been also reported. Three forms of Leishmaniasis are known: a- Cutaneous Leishmaniasis (CL); b-Mucocutaneous Leishmaniasis; c- Visceral Leishmaniasis (VL). The visceral form of Leishmaniasis has an estimated incidence of 500,000 new cases. Cytokines and chemokines primarily orchestrate leukocyte recruitment to the areas of leishmania infection, and they are critical mediators of immune and inflammatory responses, in particular of the induction of Interferon (IFN)-γ and IFN-γ dependent chemokines. Skin biopsies from patients with CL showed higher expression of interferon-γ-induced protein (IP)-10, in recent lesions than in late lesions. Following L. braziliensis infection, enhanced expression of IP-10 and its receptor, chemokine C-X-C receptor (CXCR) 3, was predominantly detected in CD14(+) monocyte; this may contribute to disease severity by increasing cellular recruitment. It has been shown that IP-10 renders protection against VL, and it is associated with a strong host-protective T helper cell (Th)1 immune response. High clinical scores were positively correlated with IP-10 expression. Furthermore IP-10 is critical for rendering a protective cellular immunity during soluble leishmanial antigen (SLA) pulsed-CpG-ODN stimulated dendritic cells (SLA-CpG-DCs) vaccination that confers protection against L. donovani infection. Further studies are needed to evaluate IP-10 in Leishmaniosis, and to evaluate it as a potential therapeutic target.

Contact dermatitis and interferon-γ dependent chemokines.

Inflammation of the skin is the pathological base of contact dermatitis (CD), and cytokines are very important in its pathogenesis. Recently it has been shown that interferon (IFN)-γ, and the IFN-γ dependent chemokines, monokine induced by IFN-γ (MIG), IFN-γ-induced protein 10 (IP-10), and IFN-inducible T cell alpha chemoattractant (I-TAC), play an important role in CD. Allergic CD (ACD) is a T-cell-mediated disease in which expression of a distinct repertoire of chemokines results in the recruitment of effector T cells into the skin. An increased expression of MIG, IP-10 and I-TAC in the skin has been observed by many studies in ACD, but not in irritant CD. The IFN-γ dependent chemokines are produced by keratinocytes, mainly during the clinically inflammatory phase of ACD. Also chemokine (C-X-C motif) receptor (CXCR) 3, the common receptor of the three IFN-γ dependent chemokines, is upregulated in chemical-induced allergic skin responses when compared with irritant skin responses. However, other studies have shown a low level increase of IP-10 in irritant sodium dodecyl sulphate dermatitis. The above mentioned results show that although skin inflammation contact sensitizer-induced is similar to irritant-induced, the regulation of allergic inflammation-related gene MIG and IP-10, could help to discriminate skin sensitization from chemically irritation.

Interferon-γ-induced protein 10 in Dengue Virus infection.

Dengue virus (DENV) infection causes dengue fever, dengue hemorrhagic fever, or dengue shock syndrome. Interferons (IFNs), and IFN-γ dependent chemokines, chemokine (C-X-C motif) ligand (CXCL)10/IFN-γ-induced protein 10 (IP-10), CXCL9/MIG and CXCL11/I-TAC, and their common receptor chemokine (C-X-C motif) receptor (CXCR)3 are induced by DENV infection; however it has been shown that the latter two could not compensate for the absence of IP-10. This paper reviews studies about DENV and IP-10. Evidences show the importance of IP-10 induction during DENV infection, in macrophages, lymphocytes, hepatic cells, denritic cells, in skin and in the brain. Furthermore it has been shown that chemokines IP-10, I-TAC and their receptor CXCR3 are involved in severity of dengue; in fact, pulmonary effusion or ascites, painful hepatomegaly or aspartate aminotransferase increase, are correlated with IP-10 levels. It has been also demonstrated that IP-10 was more elevated in subjects who subsequently developed dengue hemorrhagic fever or dengue shock syndrome. It has been also shown that IP-10 has a direct action in control of dengue viral replication. Furthermore IP-10 circulating levels may be used to discriminate dengue fever from other febbrile diseases. This is of particular importance in certain situations, for example to discriminate occupationally acquired dengue, in patients with febbrile disorders coming from endemic countries. These studies suggested that these chemokines can be used as potential biomarkers for differential diagnosis and the disease progression, while others can be used to control dengue viral replication, thus representing a viable targets for drug therapy.

Mesothelioma and interferon-γ-dependent chemokine IP-10.

Recently it has been shown that interferon (IFN)-γ plays an important role in mesothelioma, mediated by the main IFN-γ dependent chemokines, chemokine (C-X-C motif) ligand (CXCL)10/IFN-γ- induced protein 10 (IP-10). IP-10 is up-regulated in malignant mesothelioma (MM), suggesting a relationship with development of these tumors. Nanoparticles containing nickel, that increase the risk for pleural diseases, induced increased levels of IP-10 in rat pleural mesothelial cells. Chemokine (C-X-C motif) receptor (CXCR)3 expression in CD4(+) T cells from pleural plaques and MMs was significantly decreased compared with that from healthy donors suggesting that CXCR3, IFN-γ, and IP-10 may be candidates to detect and monitor disease status. In a patient with asbestos-related malignant pleural mesothelioma the oncolytic adenovirus (ONCOS-102) induced prominent infiltration of CD8(+) lymphocytes to tumor, marked induction of systemic antitumor CD8(+) T-cells and expression of IP-10. Furthermore, increased IP- 10 concentrations were observed in the sera of the asbestos-exposed workers and were associated with the severity of asbestos-related diseases. These findings suggest that IP-10 chemokine may have a prognostic role in the progression of asbestos-related diseases and could be used for the health surveillance of either workers with an occupational history of asbestos exposure or patients affected by nonmalignant asbestos-related diseases.