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Immunity  2013;39(6):1003-1018.
Interleukin-1 (IL-1) is a central mediator of innate immunity and inflammation. The IL-1 family includes 7 ligands with agonist activity (IL-1α and β, IL-18, IL-33, IL-36α, β, γ), three receptor antagonists (IL-1Ra, IL-36Ra, IL-38) and an anti-inflammatory cytokine (IL-37). Members of the IL-1 Receptor (IL-1R) family include 6 receptor chains forming 4 signaling receptor complexes, two decoy receptors (IL-1R2, IL-18BP) and two negative regulators (TIR8 or SIGIRR, IL-1RAcPb). A tight regulation via receptor antagonists, decoy receptors and signaling inhibitors ensures a balance between amplification of innate immunity and uncontrolled inflammation. All cells of the innate immune system express and/or are affected by IL-1 family members. Moreover, IL-1 family members play a key role in the differentiation and function of polarized innate and adaptive lymphoid cells. Here we will review the key properties of IL-1 family members, with emphasis on pathways of negative regulation and orchestration of innate and adaptive immunity.
PMCID: PMC3933951  PMID: 24332029
2.  Systemic pentraxin-3 levels reflect vascular enhancement and progression in Takayasu arteritis 
Progression of arterial involvement is often observed in patients with Takayasu arteritis (TA) thought to be in remission. This reflects the failure of currently used biomarkers and activity criteria to detect smouldering inflammation occurring within arterial wall. Pentraxin-3 (PTX3) is a soluble pattern recognition receptor produced at sites of inflammation and could reveal systemic as well as localized inflammatory processes. We verified whether the blood concentrations of PTX3 and of C-reactive protein (CRP) in patients with Takayasu arteritis (TA) might reflect vascular wall involvement, as assessed by signal enhancement after contrast media administration, and the progression of arterial involvement.
A cross-sectional single-centre study was carried out on 42 patients with TA that comprised assessment of PTX3, of CRP and erythrocyte sedimentation velocity (ESR). In total, 20 healthy controls and 20 patients with Systemic Lupus Erythematous (SLE) served as controls. Vascular imaging was carried out by magnetic resonance angiography, doppler ultrasonography and computed tomography angiography.
Patients with TA and SLE had higher plasmatic PTX3 and CRP concentrations than healthy controls (P = 0.009 and 0.017, respectively). PTX3 levels did not correlate with those of CRP. Patients with active systemic TA had significantly higher concentrations of CRP but similar levels of PTX3 than patients with quiescent disease. In contrast, patients with vascular inflammation detectable at imaging had higher PTX3 concentrations (P = 0.016) than those in which vessel inflammation was not evident, while CRP levels were similar. The concentration of PTX3 but not that of CRP was significantly higher in TA patients with worsening arterial lesions that were not receiving antagonists of tumor necrosis factor-α or interleukin-6.
Arterial inflammation and progression of vascular involvement influence plasma PTX3 levels in TA, while levels of CRP accurately reflect the burden of systemic inflammation. These results support the contention that PTX3 reflects different aspects of inflammation than CRP and might represent a biomarker of actual arteritis in TA.
PMCID: PMC4245785  PMID: 25394473
3.  Alveolar pentraxin 3 as an early marker of microbiologically confirmed pneumonia: a threshold-finding prospective observational study 
Critical Care  2014;18(5):562.
Timely diagnosis of pneumonia in intubated critically ill patients is rather challenging. Pentraxin 3 (PTX3) is an acute-phase mediator produced by various cell types in the lungs. Animal studies have shown that, during pneumonia, PTX3 participates in fine-tuning of inflammation (for example, microbial clearance and recruitment of neutrophils). We previously described an association between alveolar PTX3 and lung infection in a small group of intubated patients. The aim of the present study was to determine a threshold level of alveolar PTX3 with elevated sensitivity and specificity for microbiologically confirmed pneumonia.
We recruited 82 intubated patients from two intensive care units (San Gerardo Hospital, Monza, Italy, and Massachusetts General Hospital, Boston, MA, USA) undergoing bronchoalveolar lavage (BAL) as per clinical decision. We collected BAL fluid and plasma samples, together with relevant clinical and microbiological data. We assayed PTX3 and soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) in BAL fluid and PTX3, sTREM-1, C-reactive protein (CRP) and procalcitonin (PCT) in plasma. Two blinded independent physicians reviewed patient data to confirm pneumonia. We determined the PTX3 threshold in BAL fluid for pneumonia and compared it to other biomarkers.
Microbiologically confirmed pneumonia of bacterial (n =12), viral (n =4) or fungal (n =8) etiology was diagnosed in 24 patients (29%). PTX3 levels in BAL fluid predicted pneumonia with an area under the receiving operator curve of 0.815 (95% CI =0.710 to 0.921, P <0.0001), whereas none of the other biomarkers were effective. In particular, PTX3 levels ≥1 ng/ml in BAL fluid predicted pneumonia in univariate analysis (β =2.784, SE =0.792, P <0.001) with elevated sensitivity (92%), specificity (60%) and negative predictive value (95%). Net reclassification index PTX3 values ≥1 ng/ml in BAL fluid for pneumonia indicated gain in sensitivity and/or specificity vs. all other mediators. These results did not change when we limited our analyses only to confirmed cases of bacterial pneumonia. Moreover, when we considered only the 70 patients who fulfilled the clinical criteria for the diagnosis of pneumonia at BAL fluid sampling, the diagnostic accuracy of PTX levels was confirmed in univariate and ROC curve analysis.
In this hypothesis-generating convenience sample, a PTX3 level ≥1 ng/ml in BAL fluid was discriminative of microbiologically confirmed pneumonia in mechanically ventilated patients.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-014-0562-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4219103  PMID: 25314919
4.  Exposure to Endocrine Disrupters and Nuclear Receptor Gene Expression in Infertile and Fertile Women from Different Italian Areas 
Within the PREVIENI project, infertile and fertile women were enrolled from metropolitan, urban and rural Italian areas. Blood/serum levels of several endocrine disrupters (EDs) (perfluorooctane sulfonate, PFOS; perfluorooctanoic acid, PFOA; di-2-ethylhexyl-phthalate, DEHP; mono-(2-ethylhexyl)-phthalate, MEHP; bisphenol A, BPA) were evaluated concurrently with nuclear receptors (NRs) gene expression levels (ERα, ERβ, AR, AhR, PPARγ, PXR) in peripheral blood mononuclear cells (PBMCs). Infertile women from the metropolitan area displayed significantly higher levels of: BPA compared to fertile women (14.9 vs. 0.5 ng/mL serum); BPA and MEHP compared to infertile women from urban and rural areas; enhanced expression levels of NRs, except PPARγ. Infertile women from urban and rural areas had PFOA levels significantly higher than those from metropolitan areas. Our study indicates the relevance of the living environment when investigating the exposure to EDs and the modulation of the NR panel in PBMC as a suitable biomarker of the effect, to assess the EDs impact on reproductive health.
PMCID: PMC4210972  PMID: 25268510
human exposure; women infertility; PFOS; PFOA; BPA; DEHP; MEHP; biomarkers
6.  Response of CFTR-Deficient Mice to Long-Term chronic Pseudomonas aeruginosa Infection and PTX3 Therapy 
The Journal of Infectious Diseases  2012;208(1):130-138.
Background. In cystic fibrosis (CF) patients, chronic lung infection and inflammation due to Pseudomonas aeruginosa contribute to the decline of lung function. The increased prevalence of multidrug resistance among bacteria and the adverse effects of antiinflammatory agents highlight the need for alternative therapeutic approaches that should be tested in a relevant animal model.
Methods. Gut-corrected CF and non-CF mice were chronically infected with a multidrug-resistant P. aeruginosa strain and treated with the long pentraxin PTX3. Body weight, bacterial count, inflammation, and lung pathology were evaluated after 12 days. PTX3 localization in CF sputum specimens was analyzed by immunofluorescence.
Results. Chronic P. aeruginosa infection developed similarly in CF and non-CF mice but differed in terms of the inflammatory response. Leukocyte recruitment in the airways, cytokine levels, and chemokine levels were significantly higher in CF mice, compared with non-CF mice. PTX3 treatment, which facilitates phagocytosis of pathogens, reduced P. aeruginosa colonization and restored airway inflammation in CF mice to levels observed in non-CF mice. The presence of PTX3 in CF sputum, in leukocytes, or bound to P. aeruginosa macrocolonies, as well as previous data on PTX3 polymorphisms in colonized CF patients, confirm the relevance of this molecule.
Conclusions. These findings represent a step forward in demonstrating the therapeutic potential of PTX3 in CF.
PMCID: PMC4055833  PMID: 23087427
Respiratory Tract Infections; Pseudomonas Infection; inflammation; Mouse Model; Cystic Fibrosis; PTX3
7.  Bisphenol a and the female reproductive tract: an overview of recent laboratory evidence and epidemiological studies 
Bisphenol A (BPA) is a high production volume monomer used for making a wide variety of polycarbonate plastics and resins. A large body of evidence links BPA to endocrine disruption in laboratory animals, and a growing number of epidemiological studies support a link with health disorders in humans. The aim of this review is to summarize the recent experimental studies describing the effects and mechanisms of BPA on the female genital tract and to compare them to the current knowledge regarding the impact of BPA impact on female reproductive health. In particular, BPA has been correlated with alterations in hypothalamic-pituitary hormonal production, reduced oocyte quality due to perinatal and adulthood exposure, defective uterine receptivity and the pathogenesis of polycystic ovary syndrome. Researchers have reported conflicting results regarding the effect of BPA on premature puberty and endometriosis development. Experimental studies suggest that BPA’s mechanism of action is related to life stage and that its effect on the female reproductive system may involve agonism with estrogen nuclear receptors as well as other mechanisms (steroid biosynthesis inhibition). Notwithstanding uncertainties and knowledge gaps, the available evidence should be seen as a sufficient grounds to take precautionary actions against excess exposure to BPA.
PMCID: PMC4019948  PMID: 24886252
Bisphenol A; Endocrine disruptors; Fertility; Reproductive health; Genital tract
8.  Inflammation, wound repair, and fibrosis: reassessing the spectrum of tissue injury and resolution 
The Journal of pathology  2013;229(2):141-144.
Estimates from various disease-specific registries suggest that chronic inflammatory and fibrotic disorders affect a large proportion of the world’s population, yet therapies for these conditions are largely ineffective. Recent advances in our collective understanding of mechanisms underlying both physiological and pathological repair of tissue injury are informing new clinical approaches to deal with various human inflammatory and fibrotic diseases. This 2013 Annual Review Issue of The Journal of Pathology offers an up-to-date glimpse of ongoing research in the fields of inflammation, wound healing, and tissue fibrosis, and highlights novel pathways and mechanisms that may be exploited to provide newer, more effective treatments to patients worldwide suffering from these conditions.
PMCID: PMC3996448  PMID: 23097196
inflammation; fibrosis; wound healing
9.  Transumbilical laparoscopic-assisted appendectomy in children: Clinical and surgical outcomes 
The aim of this paper is to present and describe transumbilical laparoscopic-assisted appendectomy in children, focusing on its technical aspects and clinical and surgical outcomes. The surgical charts of all patients aged between 0 and 14 years treated with transumbilical laparoscopic-assisted appendectomy admitted to the authors’ institution from January 2009 to September 2013 with a diagnosis of suspected appendicitis following clinical, laboratory and ultrasound findings were reviewed. Operating time, intraoperative findings, need for conversion or for additional trocars, and surgical complications were reported. During the study period, 120 patients aged between 6 and 14 years (mean age: 9.9 years), 73 females (61%) and 47 males (39%), were treated with transumbilical laparoscopic-assisted appendectomy. There were 37 cases of hyperemic appendicitis (subserosal and retrocecal), 74 cases of phlegmonous appendicitis and 9 cases of perforated gangrenous appendicitis. It was not possible to establish a correlation between grade of appendicitis and mean operating time (P > 0.05). Eleven cases (9%) needed the use of one additional trocar, while 8 patients (6%) required conversion to the standard laparoscopic technique with the use of two additional trocars. No patient was converted to the open technique. Transumbilical laparoscopic-assisted appendectomy is a safe technique in children and it could be used by surgeons who want to approach other minimally invasive techniques.
PMCID: PMC3985149  PMID: 24748916
Appendectomy; Children; Minimally invasive surgery; Transumbilical; Procedure
10.  Selective Activation of Human Dendritic Cells by OM-85 through a NF-kB and MAPK Dependent Pathway 
PLoS ONE  2013;8(12):e82867.
OM-85 (Broncho-Vaxom®, Broncho-Munal®, Ommunal®, Paxoral®, Vaxoral®), a product made of the water soluble fractions of 21 inactivated bacterial strain patterns responsible for respiratory tract infections, is used for the prevention of recurrent upper respiratory tract infections and acute exacerbations in chronic obstructive pulmonary disease patients. OM-85 is able to potentiate both innate and adaptive immune responses. However, the molecular mechanisms responsible for OM-85 activation are still largely unknown. Purpose of this study was to investigate the impact of OM-85 stimulation on human dendritic cell functions. We show that OM-85 selectively induced NF-kB and MAPK activation in human DC with no detectable action on the interferon regulatory factor (IRF) pathway. As a consequence, chemokines (i.e. CXCL8, CXCL6, CCL3, CCL20, CCL22) and B-cell activating cytokines (i.e. IL-6, BAFF and IL-10) were strongly upregulated. OM-85 also synergized with the action of classical pro-inflammatory stimuli used at suboptimal concentrations. Peripheral blood mononuclear cells from patients with COPD, a pathological condition often associated with altered PRR expression pattern, fully retained the capability to respond to OM-85. These results provide new insights on the molecular mechanisms of OM-85 activation of the immune response and strengthen the rational for its use in clinical settings.
PMCID: PMC3875422  PMID: 24386121
11.  Interaction of C1q with IgG1, C-reactive Protein and Pentraxin 3: Mutational Studies Using Recombinant Globular Head Modules of Human C1q A, B, and C Chains† 
Biochemistry  2006;45(13):10.1021/bi052646f.
C1q is the first subcomponent of the classical complement pathway that can interact with a range of biochemically and structurally diverse self and nonself ligands. The globular domain of C1q (gC1q), which is the ligand-recognition domain, is a heterotrimeric structure composed of the C-terminal regions of A (ghA), B (ghB), and C (ghC) chains. The expression and functional characterization of ghA, ghB, and ghC modules have revealed that each chain has specific and differential binding properties toward C1q ligands. It is largely considered that C1q–ligand interactions are ionic in nature; however, the complementary ligand-binding sites on C1q and the mechanisms of interactions are still unclear. To identify the residues on the gC1q domain that are likely to be involved in ligand recognition, we have generated a number of substitution mutants of ghA, ghB, and ghC modules and examined their interactions with three selected ligands: IgG1, C-reactive protein (CRP), and pentraxin 3 (PTX3). Our results suggest that charged residues belonging to the apex of the gC1q heterotrimer (with participation of all three chains) as well as the side of the ghB are crucial for C1q binding to these ligands, and their contribution to each interaction is different. It is likely that a set of charged residues from the gC1q surface participate via different ionic and hydrogen bonds with corresponding residues from the ligand, instead of forming separate binding sites. Thus, a recently proposed model suggesting the rotation of the gC1q domain upon ligand recognition may be extended to C1q interaction with CRP and PTX3 in addition to IgG1.
PMCID: PMC3874390  PMID: 16566583
12.  Echocardiography, Spirometry, and Systemic Acute-Phase Inflammatory Proteins in Smokers with COPD or CHF: An Observational Study 
PLoS ONE  2013;8(11):e80166.
Chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF) may coexist in elderly patients with a history of smoking. Low-grade systemic inflammation induced by smoking may represent the link between these 2 conditions. In this study, we investigated left ventricular dysfunction in patients primarily diagnosed with COPD, and nonreversible airflow limitation in patients primarily diagnosed with CHF. The levels of circulating high-sensitive C-reactive protein (Hs-CRP), pentraxin 3 (PTX3), interleukin-1β (IL-1 β), and soluble type II receptor of IL-1 (sIL-1RII) were also measured as markers of systemic inflammation in these 2 cohorts. Patients aged ≥50 years and with ≥10 pack years of cigarette smoking who presented with a diagnosis of stable COPD (n=70) or stable CHF (n=124) were recruited. All patients underwent echocardiography, N-terminal pro-hormone of brain natriuretic peptide measurements, and post-bronchodilator spirometry. Plasma levels of Hs-CRP, PTX3, IL-1 β, and sIL-1RII were determined by using a sandwich enzyme-linked immuno-sorbent assay in all patients and in 24 healthy smokers (control subjects). Although we were unable to find a single COPD patient with left ventricular dysfunction, we found nonreversible airflow limitation in 34% of patients with CHF. On the other hand, COPD patients had higher plasma levels of Hs-CRP, IL1 β, and sIL-1RII compared with CHF patients and control subjects (p < 0.05). None of the inflammatory biomarkers was different between CHF patients and control subjects. In conclusion, although the COPD patients had no evidence of CHF, up to one third of patients with CHF had airflow limitation, suggesting that routine spirometry is warranted in patients with CHF, whereas echocardiography is not required in well characterized patients with COPD. Only smokers with COPD seem to have evidence of systemic inflammation.
PMCID: PMC3823838  PMID: 24244639
14.  Increased long-term expression of pentraxin 3 in irradiated human arteries and veins compared to internal controls from free tissue transfers 
Clinical studies have shown that radiotherapy increases the risk of cardiovascular disease at irradiated sites years after exposure. However, there is a lack of biological explanations in humans. We therefore examined human blood vessels exposed to radiotherapy and studied C-reactive protein (CRP) and pentraxin 3 (PTX3), a new marker for adverse cardiovascular outcome dependent on TNF- alpha (TNFα) or interleukin-1beta (IL-1β) expression.
Pairs of irradiated and non-irradiated human conduit arteries and veins were harvested from the same patient during autologous free tissue transfer for cancer-reconstruction at a median time of 48 weeks after radiotherapy. Differential gene expression was studied using qRT-PCR, confirmed by immunohistochemistry and cellular origins determined by immunofluorescence.
Gene expression in irradiated arteries compared to non-irradiated showed a consistent up-regulation of PTX3 in all patients and in a majority of veins (p < 0.001). Both TNFα and IL-1β were increased in irradiated compared to non-irradiated arteries (p < 0.01) and IL-1β correlated to the PTX3 expression (p = 0.017). Immunohistochemical and immunofluorescence staining confirmed an increased expression of PTX3 in endothelial cells, macrophages and smooth muscle cells.
The sustained expression of PTX3 in arteries and veins tie biological evidence in humans to clinical studies and encourage further exploration of innate immunity in the pathogenesis of a radiation-induced vasculopathy.
PMCID: PMC3849367  PMID: 24060373
PTX3; CRP; Radiotherapy; Human; Blood vessels; Gene expression; Cardiovascular disease; Atherosclerosis; Stroke and neck
15.  Human adipose tissue macrophages display activation of cancer-related pathways 
The Journal of Biological Chemistry  2012;287(26):21904-21913.
Obesity is associated with a significantly increased risk for cancer suggesting that adipose tissue dysfunctions might play a crucial role therein. Macrophages play important roles in adipose tissue as well as in cancers. Here, we studied whether human adipose tissue macrophages (ATM) modulate cancer cell function.
Therefore, ATM were isolated and compared to monocyte-derived macrophages (MDM) from the same obese patients. ATM, but not MDM, were found to secrete factors inducing inflammation and lipid accumulation in human T47D and HT-29 cancer cells. Gene expression profile comparison of ATM and MDM revealed over-expression of functional clusters, such as cytokine-cytokine receptor interaction (especially CXC-chemokine) signalling as well as cancer-related pathways, in ATM. Comparison with gene expression profiles of human tumour-associated macrophages (TAM) showed that ATM, but not MDM resemble TAM. Indirect co-culture experiments demonstrated that factors secreted by pre-adipocytes, but not mature adipocytes, confer an ATM-like phenotype to MDM. Finally, the concentrations of ATM secreted factors related to cancer are elevated in serum of obese subjects. In conclusion, ATM may thus modulate the cancer cell phenotype.
PMCID: PMC3381151  PMID: 22511784
Adipocytes; cytology; Adipose Tissue; metabolism; Azo Compounds; pharmacology; Cell Line, Tumor; Chemokines; metabolism; Disease Progression; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; methods; Inflammation; Macrophages; cytology; metabolism; Neoplasms; metabolism; Obesity; metabolism; Oligonucleotide Array Sequence Analysis; Phenotype; macrophages; obesity; cancer; adipose tissue; chemokines
16.  Future perspectives in melanoma research. Meeting report from the “Melanoma Bridge. Napoli, December 2nd-4th 2012” 
Recent insights into the genetic and somatic aberrations have initiated a new era of rapidly evolving targeted and immune-based treatments for melanoma. After decades of unsuccessful attempts to finding a more effective cure in the treatment of melanoma now we have several drugs active in melanoma. The possibility to use these drugs in combination to improve responses to overcome the resistance, to potentiate the action of immune system with the new immunomodulating antibodies, and identification of biomarkers that can predict the response to a particular therapy represent new concepts and approaches in the clinical management of melanoma. The third “Melanoma Research: “A bridge from Naples to the World” meeting, shortened as “Bridge Melanoma Meeting” took place in Naples, December 2 to 4th, 2012. The four topics of discussion at this meeting were: advances in molecular profiling and novel biomarkers, combination therapies, novel concepts toward integrating biomarkers and therapies into contemporary clinical management of patients with melanoma across the entire spectrum of disease stage, and the knowledge gained from the biology of tumor microenvironment across different tumors as a bridge to impact on prognosis and response to therapy in melanoma. This international congress gathered more than 30 international faculty members who in an interactive atmosphere which stimulated discussion and exchange of their experience regarding the most recent advances in research and clinical management of melanoma patients.
PMCID: PMC3681569  PMID: 23731854
17.  Correlation of Endocrine Disrupting Chemicals Serum Levels and White Blood Cells Gene Expression of Nuclear Receptors in a Population of Infertile Women 
Significant evidence supports that many endocrine disrupting chemicals could affect female reproductive health. Aim of this study was to compare the internal exposure to bisphenol A (BPA), perfluorooctane sulphonate (PFOS), perfluorooctanoic acid (PFOA), monoethylhexyl phthalate (MEHP), and di(2-ethylhexyl) phthalate (DEHP) in serum samples of 111 infertile women and 44 fertile women. Levels of gene expression of nuclear receptors (ERα, ERβ, AR, AhR, PXR, and PPARγ) were also analyzed as biomarkers of effective dose. The percentage of women with BPA concentrations above the limit of detection was significantly higher in infertile women than in controls. No statistically significant difference was found with regard to PFOS, PFOA, MEHP and DEHP. Infertile patients showed gene expression levels of ERα, ERβ, AR, and PXR significantly higher than controls. In infertile women, a positive association was found between BPA and MEHP levels and ERα, ERβ, AR, AhR, and PXR expression. PFOS concentration positively correlated with AR and PXR expression. PFOA levels negatively correlated with AhR expression. No correlation was found between DEHP levels and all evaluated nuclear receptors. This study underlines the need to provide special attention to substances that are still widely present in the environment and to integrate exposure measurements with relevant indicators of biological effects.
PMCID: PMC3654366  PMID: 23710174
18.  Trabectedin 
Oncoimmunology  2013;2(6):e24614.
Tumor-associated macrophages (TAMs) and other myeloid cells that infiltrate neoplastic lesions promote tumor progression and are associated with poor patient prognosis. We have recently demonstrated that trabectedin, a licensed and commercially available anticancer agent, is selectively cytotoxic for TAMs and their circulating precursors (monocytes). The macrophage-depleting effect of trabectedin is a key component of its antitumor activity.
PMCID: PMC3716756  PMID: 23894721
tumor-associated macrophages; chemotherapy; micro-environment; angiogenesis; marine drug
19.  Serum Amyloid P Is a Sialylated Glycoprotein Inhibitor of Influenza A Viruses 
PLoS ONE  2013;8(3):e59623.
Members of the pentraxin family, including PTX3 and serum amyloid P component (SAP), have been reported to play a role in innate host defence against a range of microbial pathogens, yet little is known regarding their antiviral activities. In this study, we demonstrate that human SAP binds to human influenza A virus (IAV) strains and mediates a range of antiviral activities, including inhibition of IAV-induced hemagglutination (HA), neutralization of virus infectivity and inhibition of the enzymatic activity of the viral neuraminidase (NA). Characterization of the anti-IAV activity of SAP after periodate or bacterial sialidase treatment demonstrated that α(2,6)-linked sialic acid residues on the glycosidic moiety of SAP are critical for recognition by the HA of susceptible IAV strains. Other proteins of the innate immune system, namely human surfactant protein A and porcine surfactant protein D, have been reported to express sialylated glycans which facilitate inhibition of particular IAV strains, yet the specific viral determinants for recognition of these inhibitors have not been defined. Herein, we have selected virus mutants in the presence of human SAP and identified specific residues in the receptor-binding pocket of the viral HA which are critical for recognition and therefore susceptibility to the antiviral activities of SAP. Given the widespread expression of α(2,6)-linked sialic acid in the human respiratory tract, we propose that SAP may act as an effective receptor mimic to limit IAV infection of airway epithelial cells.
PMCID: PMC3609861  PMID: 23544079
Journal of hepatology  2011;56(3):731-733.
PMCID: PMC3580217  PMID: 22005588
autoimmunity; innate immunity; macrophages; biliary tree; apoptosis
21.  Long Pentraxin PTX3 Exacerbates Pressure Overload–Induced Left Ventricular Dysfunction 
PLoS ONE  2013;8(1):e53133.
Left ventricular hypertrophy is enhanced by an inflammatory state and stimulation of various cytokines. Pentraxin 3 (PTX3) is rapidly produced in response to inflammatory signals, and high plasma PTX3 levels are seen in patients with heart failure. This study aimed to examine the influence of PTX3 on cardiac hypertrophy and left ventricular dysfunction with respect to pressure overload.
Methods and Results
PTX3 systemic knockout (PTX3-KO) mice, transgenic mice with cardiac-specific overexpression of PTX3 (PTX3-TG), and the respective wild-type (WT) littermate mice were subjected to transverse aortic constriction (TAC) or a sham operation. Cardiac PTX3 expression increased after TAC in WT mice. In vitro, hydrogen peroxide induced the expression of PTX3 in both cardiac myocytes and cardiac fibroblasts. Recombinant PTX3 phosphorylated extracellular signal–regulated kinase 1/2 (ERK1/2) in cardiac fibroblasts. Phosphorylation of cardiac ERK1/2 and nuclear factor kappa-B after TAC was attenuated in the PTX3-KO mice but was enhanced in the PTX3-TG mice compared with WT mice. Interleukin-6 and connective tissue growth factor production was lower in the PTX3-KO mice than in the WT mice, but this was augmented in the PTX3-TG mice than in the WT mice. Echocardiography revealed that adverse remodeling with left ventricular dysfunction, as well as with increased interstitial fibrosis, was enhanced in PTX3-TG mice, while these responses were suppressed in PTX3-KO mice.
The local inflammatory mediator PTX3 directly modulates the hypertrophic response and ventricular dysfunction following an increased afterload.
PMCID: PMC3553104  PMID: 23372656
22.  Decoys and Regulatory “Receptors” of the IL-1/Toll-Like Receptor Superfamily 
Members of the IL-1 family play a key role in innate and adaptive immunity and in the pathogenesis of diverse diseases. Members of IL-1R like receptor (ILR) family include signaling molecules and negative regulators. The latter include decoy receptors (IL-1RII; IL-18BP) and “receptors” with regulatory function (TIR8/SIGIRR; IL-1RAcPb; DIGIRR). Structural considerations suggest that also TIGIRR-1 and IL-1RAPL may have regulatory function. The presence of multiple pathways of negative regulation of members of the IL-1/IL-1R family emphasizes the need for a tight control of members of this fundamental system.
PMCID: PMC3705552  PMID: 23847621
cytokine; interleukin-1; inflammation; decoy receptor
23.  Ligands and Receptors of the Interleukin-1 Family in Immunity and Disease 
PMCID: PMC3834610  PMID: 24312101
interleukin-1; decoy receptor; inflammation; innate immunity; adaptive immunity; autoinflammatory diseases
24.  Macrophage plasticity and polarization: in vivo veritas 
Diversity and plasticity are hallmarks of cells of the monocyte-macrophage lineage. In response to IFNs, Toll-like receptor engagement, or IL-4/IL-13 signaling, macrophages undergo M1 (classical) or M2 (alternative) activation, which represent extremes of a continuum in a universe of activation states. Progress has now been made in defining the signaling pathways, transcriptional networks, and epigenetic mechanisms underlying M1-M2 or M2-like polarized activation. Functional skewing of mononuclear phagocytes occurs in vivo under physiological conditions (e.g., ontogenesis and pregnancy) and in pathology (allergic and chronic inflammation, tissue repair, infection, and cancer). However, in selected preclinical and clinical conditions, coexistence of cells in different activation states and unique or mixed phenotypes have been observed, a reflection of dynamic changes and complex tissue-derived signals. The identification of mechanisms and molecules associated with macrophage plasticity and polarized activation provides a basis for macrophage-centered diagnostic and therapeutic strategies.
PMCID: PMC3287223  PMID: 22378047
25.  Influence of Pentraxin 3 (PTX3) Genetic Variants on Myocardial Infarction Risk and PTX3 Plasma Levels 
PLoS ONE  2012;7(12):e53030.
PTX3 is a long pentraxin of the innate immune system produced by different cell types (mononuclear phagocytes, dendritic cells, fibroblasts and endothelial cells) at the inflammatory site. It appears to have a cardiovascular protective function by acting on the immune-inflammatory balance in the cardiovascular system. PTX3 plasma concentration is an independent predictor of mortality in patients with acute myocardial infarction (AMI) but the influence of PTX3 genetic variants on PTX3 plasma concentration has been investigated very little and there is no information on the association between PTX3 variations and AMI. Subjects of European origin (3245, 1751 AMI survivors and 1494 controls) were genotyped for three common PTX3 polymorphisms (SNPs) (rs2305619, rs3816527, rs1840680). Genotype and allele frequencies of the three SNPs and the haplotype frequencies were compared for the two groups. None of the genotypes, alleles or haplotypes were significantly associated with the risk of AMI. However, analysis adjusted for age and sex indicated that the three PTX3 SNPs and the corresponding haplotypes were significantly associated with different PTX3 plasma levels. There was also a significant association between PTX3 plasma concentrations and the risk of all-cause mortality at three years in AMI patients (OR 1.10, 95% CI: 1.01–1.20, p = 0.02). Our study showed that PTX3 plasma levels are influenced by three PTX3 polymorphisms. Genetically determined high PTX3 levels do not influence the risk of AMI, suggesting that the PTX3 concentration itself is unlikely to be even a modest causal factor for AMI. Analysis also confirmed that PTX3 is a prognostic marker after AMI.
PMCID: PMC3532160  PMID: 23285251

Results 1-25 (63)