Hernández Caselles, Trinidad

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Hernández Caselles, Trinidad

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Hernández Caselles, Trinidad

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Universidad de Murcia. Departamento de Bioquímica y Biología Molecular"B" e Inmunología

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Peritoneal macrophage priming in cirrhosis is related to ERK phosphorylation and IL-6 secretion.
(Wiley, 2010-08-19) Ruiz Alcaraz, Antonio José; Martínez-Esparza Alvargonzález, María Concepción; Caño, Rocío; Hernández Caselles, Trinidad; Ricarti, Chiara; Llanos, Lucía; Zapater, Pedro; Martín-Orozco Santiago, María Elena; Pérez Mateo, Miguel; Such, José; García Peñarrubia, María del Pilar; Francés, Rubén; Tapia Abellán, Ana; Bioquímica y Biología Molecular B e Inmunología
Background: Bacterial infections are common complications arising in patients with cirrhosis and ascites. Translocation of bacterial DNA is a dynamic process that is associated with an increased inflammatory response and a poor prognosis in this setting. The aim of this study was to study whether peritoneal macrophages remain in a chronic primed status to allow a rapid response to subsequent events of bacterial translocation. Patients and methods: Peritoneal monocyte-derived macrophages were isolated from 25 patients with cirrhosis and non-infected ascites and compared with donor's blood monocytes. Activation cell-surface markers were screened using flow-cytometry, and the phosphorylation state of ERK 1/2, p38 MAP Kinase, PKB/Akt and transcription factors c-Jun and p65 NFκB were evaluated using Western blot. Synthesis of tumour necrosis factor alpha, interleukin 6 (IL-6) and interleukin-10 (IL-10) at baseline and in response to bacterial stimuli was evaluated using ELISA. Results: A high expression of CD54, CD86 and HLA-DR at baseline was displayed by peritoneal macrophages. Increased phosphorylated levels of ERK1/2, protein kinase B (PKB) and c-Jun, together with IL-6 production, were observed in peritoneal macrophages at baseline compared with donors' blood monocytes. A positive correlation was established between basal IL-6 levels and extracellular signal-regulated kinase (ERK) phosphorylation in peritoneal macrophages from patients with cirrhosis (r=0·9; P=0·005). Addition of lipopolysaccharide induced higher phosphorylation levels of all studied signalling intermediates than synthetic-oligodeoxydinucleotides, but similar end-stage p65 NFκB. Conclusions: A sustained immune response is present in ascitic fluid of cirrhotic patients, even in the temporal absence of bacterial antigens. This would facilitate a fast response, probably controlled by IL-6, against repeated bacterial-DNA translocation or in liver chronic inflammation.
Open Access
Cytokine profiles in cord blood in relation to prenatal traffic-related air pollution: The NELA cohort
(Wiley, 2022-02) García-Serna, Azahara M.; Jiménez-Guerrero, Pedro; Cantero-Cano, Esther; Muñoz-García, María; Molina-Ruano, María Dolores; Rojo-Atenza, Encarna; Hernández Caselles, Trinidad; Martín-Orozco Santiago, María Elena; Morales Bartolomé, Eva; Pérez Fernández, Virginia; García-Marcos Álvarez, Luis Vicente; Ciencias Sociosanitarias
Background: Outdoor air pollution may disturb immune system development. We investigated whether gestational exposure to traffic-related air pollutants (TRAP) is associated with unstimulated cytokine profiles in newborns. Methods: Data come from 235 newborns of the NELA cohort. Innate response-related cytokines (IL-6, IFN-α, IL1-β, and TNF-α), Th1-related (IFN-γ and IL-2), Th2-related (IL-4, IL-5, and IL-13), Th17-related (IL-17 and IL-23), and immunomodulatory cytokine IL-10 were quantified in the supernatant of unstimulated whole umbilical cord blood cells after 7 days of culture using the Luminex technology. Dispersion/chemical transport modeling was used to estimate long-term (whole pregnancy and trimesters) and short-term (15 days before delivery) residential exposures to traffic-related nitrogen dioxide (NO2 ), particulate matter (PM2.5 and PM10 ), and ozone (O3 ). We fitted multivariable logistic regression, Bayesian kernel machine regression (BKMR), and weighted quantile sum (WQS) regression models. Results: NO2 during the whole pregnancy increased the odds of detection of IL-1β (OR per 10 µg/m3 increase = 1.37; 95% CI, 1.02, 1.85) and IL-6 (OR per 10 µg/m3 increase = 1.32; 95% CI 1.00, 1.75). Increased odds of detected concentrations of IL-10 was found in newborns exposed during whole pregnancy to higher levels of NO2 (OR per 10 µg/m3 increase = 1.30; 95% CI 0.99, 1.69), PM10 (OR per 10 µg/m3 increase = 1.49; 95% CI 0.95, 2.33), and PM2.5 (OR per 5 µg/m3 increase = 1.56; 95% CI 0.97, 2.51). Exposure to O3 during the whole pregnancy increased the odds of detected IL-13 (OR per 10 µg/m3 increase = 1.22; 95% CI 1.01, 1.49). WQS model revealed first and third trimesters of gestation as windows of higher susceptibility. Conclusions: Gestational exposure to TRAP may increase detection of pro-inflammatory, Th2-related, and T regulatory cytokines in newborns. These changes might influence immune system responses later in life.
Open Access
Cytokine profiles in cord blood in relation to prenatal traffic-related air pollution: The NELA cohort
(2022-02-18) García-Serna, Azahara M; Jiménez-Guerrero, Pedro; Cantero-Cano, Esther; Muñoz-García, María; Molina-Ruano, María Dolores; Rojo-Atenza, Encarna; Hernández Caselles, Trinidad; Martín-Orozco Santiago, María Elena; Morales Bartolomé, Eva; Pérez Fernández, Virginia; García-Marcos Álvarez, Luis Vicente; Bioquímica y Biología Molecular B e Inmunología
Background: Outdoor air pollution may disturb immune system development. We investigated whether gestational exposure to traffic-related air pollutants (TRAP) is associated with unstimulated cytokine profiles in newborns. Methods: Data come from 235 newborns of the NELA cohort. Innate response-related cytokines (IL-6, IFN-α, IL1-β, and TNF-α), Th1-related (IFN-γ and IL-2), Th2-related (IL-4, IL-5, and IL-13), Th17-related (IL-17 and IL-23), and immunomodulatory cytokine IL-10 were quantified in the supernatant of unstimulated whole umbilical cord blood cells after 7 days of culture using the Luminex technology. Dispersion/chemical transport modeling was used to estimate long-term (whole pregnancy and trimesters) and short-term (15 days before delivery) residential exposures to traffic-related nitrogen dioxide (NO2 ), particulate matter (PM2.5 and PM10 ), and ozone (O3 ). We fitted multivariable logistic regression, Bayesian kernel machine regression (BKMR), and weighted quantile sum (WQS) regression models. Results: NO2 during the whole pregnancy increased the odds of detection of IL-1β (OR per 10 µg/m3 increase = 1.37; 95% CI, 1.02, 1.85) and IL-6 (OR per 10 µg/m3 increase = 1.32; 95% CI 1.00, 1.75). Increased odds of detected concentrations of IL-10 was found in newborns exposed during whole pregnancy to higher levels of NO2 (OR per 10 µg/m3 increase = 1.30; 95% CI 0.99, 1.69), PM10 (OR per 10 µg/m3 increase = 1.49; 95% CI 0.95, 2.33), and PM2.5 (OR per 5 µg/m3 increase = 1.56; 95% CI 0.97, 2.51). Exposure to O3 during the whole pregnancy increased the odds of detected IL-13 (OR per 10 µg/m3 increase = 1.22; 95% CI 1.01, 1.49). WQS model revealed first and third trimesters of gestation as windows of higher susceptibility. Conclusions: Gestational exposure to TRAP may increase detection of pro-inflammatory, Th2-related, and T regulatory cytokines in newborns. These changes might influence immune system responses later in life.
Open Access
The peritoneal macrophage inflammatory profile in cirrhosis depends on the alcoholic or hepatitis C viral etiology and is related to ERK phosphorylation.
(BMC, 2012-08-06) Martínez-Pascual, Cristina; Miras-López, Manuel; Such, José; Francés, Rubén; García-Peñarrubia, Pilar; Hernández Caselles, Trinidad; Martínez-Esparza Alvargonzález, María Concepción; Ruiz Alcaraz, Antonio José; Tapia Abellán, Ana; Bioquímica y Biología Molecular B e Inmunología
Background: The development of ascites in cirrhotic patients generally heralds a deterioration in their clinical status. A differential gene expression profile between alcohol- and hepatitis C virus (HCV)-related cirrhosis has been described from liver biopsies, especially those associated with innate immune responses. The aim of this work was to identify functional differences in the inflammatory profile of monocyte-derived macrophages from ascites in cirrhotic patients of different etiologies in an attempt to extrapolate studies from liver biopsies to immune cells in ascites. To this end 45 patients with cirrhosis and non-infected ascites, distributed according to disease etiology, HCV (n=15) or alcohol (n=30) were studied. Cytokines and the cell content in ascites were assessed by ELISA and flow cytometry, respectively. Cytokines and ERK phosphorylation in peritoneal monocyte-derived macrophages isolated and stimulated in vitro were also determined. Results: A different pattern of leukocyte migration to the peritoneal cavity and differences in the primed status of macrophages in cirrhosis were observed depending on the viral or alcoholic etiology. Whereas no differences in peripheral blood cell subpopulations could be observed, T lymphocyte, monocyte and polymorphonuclear cell populations in ascites were more abundant in the HCV than the alcohol etiology. HCV-related cirrhosis etiology was associated with a decreased inflammatory profile in ascites compared with the alcoholic etiology. Higher levels of IL-10 and lower levels of IL-6 and IL-12 were observed in ascitic fluid from the HCV group. Isolated peritoneal monocyte-derived macrophages maintained their primed status in vitro throughout the 24 h culture period. The level of ERK1/2 phosphorylation was higher in ALC peritoneal macrophages at baseline than in HCV patients, although the addition of LPS induced a greater increase in ERK1/2 phosphorylation in HCV than in ALC patients. Conclusions: The macrophage inflammatory status is higher in ascites of alcohol-related cirrhotic patients than in HCV-related patients, which could be related with differences in bacterial translocation episodes or regulatory T cell populations. These findings should contribute to identifying potential prognostic and/or therapeutic targets for chronic liver diseases of different etiology.
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A novel CD14high CD16high subset of peritoneal macrophages from cirrhotic patients is associated to an increased response to LPS
(Elsevier, 2016-03-01) Fernández-Fernández, María Dolores; Tristán-Manzano, María; Sánchez-Velasco, Eduardo; Miras-López, Manuel; García-Penarrubia, Pilar; Hernández Caselles, Trinidad; Martínez-Esparza Alvargonzález, María Concepción; Ruiz Alcaraz, Antonio José; Tapia Abellán, Ana; Bioquímica y Biología Molecular B e Inmunología
The aim of this study was to characterize monocyte-derived macrophages (M-DM) from blood and ascites of cirrhotic patients comparatively with those obtained from blood of healthy controls. The phenotypic profile based on CD14/CD16 expression was analyzed by flow cytometry. Cells were isolated and stimulated in vitro with LPS and heat killed Candida albicans. Phosphorylation of ERK, c-Jun, p38 MAPK, and PKB/Akt was analyzed by Western blotting. A novel CD14(high)CD16(high) M-DM subpopulation is present in ascites (∼33%). The CD14(++)CD16(+) intermediate subset is increased in the blood of cirrhotic patients (∼from 4% to 11%) and is predominant in ascites (49%), while the classical CD14(++)CD16(-) subpopulation is notably reduced in ascites (18%). Basal hyperactivation of ERK and JNK/c-Jun pathways observed in ascites M-DM correlates with CD14/CD16 high expressing subsets, while PI3K/PKB does it with the CD16 low expressing cells. In vitro LPS treatment highly increases ERK1/2, PKB/Akt and c-Jun phosphorylation, while that of p38 MAPK is decreased in M-DM from ascites compared to control blood M-DM. Stimulation of healthy blood M-DM with LPS and C. albicans induced higher phosphorylation levels of p38 than those from ascites. Regarding cytokines secretion, in vitro activated M-DM from ascites of cirrhotic patients produced significantly higher amounts of IL-6, IL-10 and TNF-α, and lower levels of IL-1β and IL-12 than control blood M-DM. In conclusion, a new subpopulation of CD14(high)CD16(high) peritoneal M-DM has been identified in ascites of cirrhotic patients, which is very sensitive to LPS stimulation.
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Role of MAP Kinases and PI3K-Akt on the cytokine inflammatory profile of peritoneal macrophages from ascites of cirrhotic patients
(Wiley, 2013-01-20) Such, José; Francés, Rubén; García-Penarrubia, Pilar; Hernández Caselles, Trinidad; Martínez-Esparza Alvargonzález, María Concepción; Ruiz Alcaraz, Antonio José; Tapia Abellán, Ana; Bioquímica y Biología Molecular B e Inmunología
Aims: Several new approaches targeting inflammation associated with different diseases are in clinical development. Objective: To explore the role played by MAPK and PI3K-Akt pathways on the release of cytokines in monocyte-derived macrophages (M-DM) obtained from the ascites of cirrhotic patients to identify novel targets for pharmaceutical intervention to prevent hepatic damage. Methods: M-DM were isolated from the ascites of cirrhotic patients and stimulated in vitro with LPS and heat-killed Candida albicans in the presence or absence of the inhibitors for MEK1, p38 MAPK, JNK and PI3K. The MAPK phosphorylation levels were determined by Western Blot. Cell culture supernatants were assayed by ELISA for TNF-α, IL-6 and IL-10. Results: The release of the pro-inflammatory cytokines IL-6 and TNF-α at baseline was more effectively reduced by the MAPK inhibitors, while the basal IL-10 anti-inflammatory cytokine secretion was only and strongly (90.3%) affected by the PI3K inhibitor. The incubation of peritoneal M-DM in the presence of LPS and C. albicans increased the release of IL-6, TNF-α and IL-10. LPS-induced pro-inflammatory cytokines secretion was more sensitive to MAPK inhibitors, whereas that induced by C. albicans was more susceptible to inhibition of PI3K. Finally, inhibition of PI3K almost completely suppressed the secretion of IL-10 in stimulated M-DM. Conclusions: These results demonstrate that pro-inflammatory cytokines release in M-DM from this clinical setting strongly depends on the MAPK signalling pathways, differs depending on the microbial stimulus added and confirms the prominent role of the PI3K-Akt pathway in the modulation of IL-10-mediated anti-inflammatory function.
Open Access
Traffic-related air pollution in utero modifies cytokine responses to stimuli of umbilical cord blood cells: a cohort study
(Elsevier, 2026-01-08) García-Serna, Azahara M.; Martín-Orozco Santiago, María Elena; Jiménez Guerrero, Pedro; Cantero-Cano, Esther; Elena, María del Carmen; Soler-Sánchez, Jesús; Hernández Caselles, Trinidad; García-Marcos Álvarez, Luis Vicente; NELA Study group; Morales Bartolomé, Eva; Física
Objective: To examine the associations between in utero exposure to traffic-related air pollutants (TRAP) and cytokine responses to stimuli in newborns. Methods: Luminex technology was used to assess cytokine responses in umbilical cord blood of 235 newborns of the NELA cohort. Samples were cultured with mitogens, pathogen associated with molecular patterns (PAMPs) stimuli and common environmental allergens. Dispersion/chemical transport modelling was used to estimate in utero residential exposures to traffic-related nitrogen dioxide (NO2), particulate matter (PM2.5 and PM10) and ozone (O3). Multivariable linear regression models were fitted. Results: Per 10 μg/m3 increase of NO2, IL-6 increased in response to mitogens Concanavalin A (12.5 %, 95 % CI: 3.6, 21.4) and Phytohemagglutinin (PHA) (14.9 %, 95 % CI: 7.3, 22.5); to PAMPs Lipopolysaccharide (LPS) (11.6 %, 95 % CI: 3.8, 19.5), Peptidoglycan (PG) (12.0 %, 95 % CI: 4.1, 20.0) and pI:C (13.0 %, 95 % CI: 4.9, 21.2); and to allergens Der pT (11.6 %, 95 % CI: 3.4, 19.9) and olive extract (9.7 %, 95 % CI: 0.4, 19.0). IL-6 response to PHA also increased in relation to PM (19.0 % per 5 μg/m3 increase in PM2.5, 95 % CI: 5.5, 32.5; and 20.2 % per 10 μg/m3 increase in PM10, 95 % CI: 6.0, 34.4). Per 10 μg/m3 increase of NO2, IFN-α responses to PHA and PG increased by 7.5 % (95 % CI: 0.6, 14.5) and 7.6 % (95 % CI: 0.1, 15.1), respectively. NO2 was also associated with an increased Th1-related IFN-γ response to Concanavalin A (7.5 % per 10 μg/m3 increase, 95 % CI: 0.1, 14.9) and decreased Th2-related IL-5 response to PAMPs PG (􀀀 6.7 %, 95 % CI: 􀀀 12.8, 􀀀 0.7) and pI:C (􀀀 7.6 %, 95 % CI: 􀀀 14.2, 􀀀 0.9). Conclusion: Prenatal exposure to TRAP may promote higher proinflammatory and Th1-related and lower Th2- related cytokine responses to stimuli in the offspring