Luís Arpa

Universitat de Barcelona

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Trends

Author Order

Document Type

Co-Authors

Antonio Celada

Universitat de Barcelona

Jorge Lloberas

Universitat de Barcelona

Annabel F. Valledor

Universitat de Barcelona

Carmé Caelles

Universitat de Barcelona

Manuel Modolell

Max Planck Institute of Immunobiology and Epigenetics

Manuel Palacı́n

Universitat de Barcelona

Concepció Soler

Universitat de Barcelona

Lorena Martín‐Jaular

Institut Curie

Joan Bertran

Universitat de Vic - Universitat Central de Catalunya

Carol McLeod

University of California, San Diego

Cooperative Institutions

Universitat de Barcelona

Institute for Research in Biomedicine

Barcelona Biomedical Research Park

Centro de Investigación Biomédica en Red

Harvard University

University of California, San Diego

Biomedical Research Institute

Massachusetts General Hospital

Universitat Autònoma de Barcelona

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Field

Selective Roles of MAPKs during the Macrophage Response to IFN-γ

The Journal of Immunology (2008)

Annabel F. Valledor Ester Sánchez‐Tilló Luís Arpa Jin Mo Park Carmé Caelles

Abstract Macrophages perform essential functions in the infection and resolution of inflammation. IFN-γ is the main endogenous macrophage Th1 type activator. The classical IFN-γ signaling pathway involves activation of Stat-1. However, IFN-γ has also the capability to activate members of the MAPK family. In primary bone marrow-derived macrophages, we have observed strong activation of p38 at early time points of IFN-γ stimulation, whereas weak activation of ERK-1/2 and JNK-1 was detected at a more delayed stage. In parallel, IFN-γ exerted repressive effects on the expression of a number of MAPK phosphatases. By using selective inhibitors and knockout models, we have explored the contributions of MAPK activation to the macrophage response to IFN-γ. Our findings indicate that these kinases regulate IFN-γ-mediated gene expression in a rather selective way: p38 participates mainly in the regulation of the expression of genes required for the innate immune response, including chemokines such as CCL5, CXCL9, and CXCL10; cytokines such as TNF-α; and inducible NO synthase, whereas JNK-1 acts on genes involved in Ag presentation, including CIITA and genes encoding MHC class II molecules. Modest effects were observed for ERK-1/2 in these studies. Interestingly, some of the MAPK-dependent changes in gene expression observed in these studies are based on posttranscriptional regulation of mRNA stability.

CIITA

CCL5

CCL22

10.4049/jimmunol.180.7.4523

Cite

Citations (98)

IFN-γ–mediated inhibition of MAPK phosphatase expression results in prolonged MAPK activity in response to M-CSF and inhibition of proliferation

Blood (2008)

Annabel F. Valledor Luís Arpa Ester Sánchez‐Tilló Mónica Comalada Cristina Casals

Growth inhibition

10.1182/blood-2007-11-123604

Cite

Citations (48)

The kinase p38α serves cell type–specific inflammatory functions in skin injury and coordinates pro- and anti-inflammatory gene expression

Nature Immunology (2008)

Chun Kim Yasuyo Sano Kristina Todorova Bradley A. Carlson Luís Arpa

Cell type

10.1038/ni.1640

Cite

Citations (257)

Macrophages require distinct arginine catabolism and transport systems for proliferation and for activation

European Journal of Immunology (2006)

Andrée Yeramian Lorena Martín‐Jaular Luís Arpa Joan Bertran Concepció Soler

In murine macrophages, as a result of arginine catabolism during activation, citruline is produced under the effect of IFN-gamma and LPS, and ornithine and polyamines by IL-4 and IL-10. For proliferation, arginine is required from the extracellular medium and is used for protein synthesis. During activation, most arginine (>95% in 6 h) was metabolized, while under proliferation only half was incorporated into proteins. Under basal conditions, this amino acid was preferentially transported by y(+)L activity. During activation, arginine transport increased drastically (4-5-fold) through y(+) cationic amino acid transporter (CAT) activity. By contrast, M-CSF induced only a modest increase in uptake (0.5-fold). The increase in arginine transport during activation, but not proliferation, was mediated by the SLC7A2/Cat2 gene. SLC7A1/Cat1 is constitutively expressed, and is not modified by proliferating or activating agents. M-CSF-dependent proliferation was not affected in the macrophages of SLC7A2 knockout mice; however, these cells showed a drastic reduction in the production of citruline or ornithine and polyamines during activation. The data show that a large increase in a specific transport system (CAT2) is necessary for activation-induced arginine metabolism, while arginine is in excess for the requirements of proliferation and a modest increase in transport occurs.

Catabolism

Amino acid transporter

10.1002/eji.200535694

Cite

Citations (89)

Arginase and polyamine synthesis are key factors in the regulation of experimental leishmaniasis in vivo

The FASEB Journal (2005)

Pascale Kropf José M. Fuentes Eva Fähnrich Luís Arpa S. Herath

Arginase 1, an enzyme induced by Th2 cytokines, is a hallmark of alternatively activated macrophages and is responsible for the hydrolysis of L-arginine into ornithine, the building block for the production of polyamines. Upregulation of arginase 1 has been observed in a variety of diseases, but the mechanisms by which arginase contributes to pathology are not well understood. We reveal here a unique role for arginase 1 in the pathogenesis of nonhealing leishmaniasis, a prototype Th2 disease, and demonstrate that the activity of this enzyme promotes pathology and uncontrolled growth of Leishmania parasites in vivo. Inhibition of arginase activity during the course of infection has a clear therapeutic effect, as evidenced by markedly reduced pathology and efficient control of parasite replication. Despite the clear amelioration of the disease, this treatment does not alter the Th2 response. To address the underlying mechanisms, the arginase-induced L-arginine catabolism was investigated and the results demonstrate that arginase regulates parasite growth directly by affecting the polyamine synthesis in macrophages.

Polyamine

Catabolism

10.1096/fj.04-3416fje

Cite

Citations (287)

Distinct Responses to IL4 in Macrophages Mediated by JNK

Cells (2023)

Luís Arpa Carlos Batlle Peijin Jiang Carmé Caelles Jorge Lloberas

IL(Interleukin)-4 is the main macrophage M2-type activator and induces an anti-inflammatory phenotype called alternative activation. The IL-4 signaling pathway involves the activation of STAT (Signal Transducer and Activator of Transcription)-6 and members of the MAPK (Mitogen-activated protein kinase) family. In primary-bone-marrow-derived macrophages, we observed a strong activation of JNK (Jun N-terminal kinase)-1 at early time points of IL-4 stimulation. Using selective inhibitors and a knockout model, we explored the contribution of JNK-1 activation to macrophages’ response to IL-4. Our findings indicate that JNK-1 regulates the IL-4-mediated expression of genes typically involved in alternative activation, such as Arginase 1 or Mannose receptor, but not others, such as SOCS (suppressor of cytokine signaling) 1 or p21Waf−1 (cyclin dependent kinase inhibitor 1A). Interestingly, we have observed that after macrophages are stimulated with IL-4, JNK-1 has the capacity to phosphorylate STAT-6 on serine but not on tyrosine. Chromatin immunoprecipitation assays revealed that functional JNK-1 is required for the recruitment of co-activators such as CBP (CREB-binding protein)/p300 on the promoter of Arginase 1 but not on p21Waf−1. Taken together, these data demonstrate the critical role of STAT-6 serine phosphorylation by JNK-1 in distinct macrophage responses to IL-4.

10.3390/cells12081127

Cite

Citations (1)

IL‐4 blocks M‐CSF‐dependent macrophage proliferation by inducing p21^Waf1 in a STAT6‐dependent way

European Journal of Immunology (2009)

Luís Arpa Annabel F. Valledor Jorge Lloberas Antonio Celada

Macrophages are recruited from the blood stream to the inflammatory loci to carry out their functional activities. In an early phase of the cell cycle, macrophages become activated by Th1-type cytokines (i.e. IFN-gamma), thereby producing several factors (cytokines, NO, etc.) and developing pro-inflammatory activities. When bacteria and apoptotic bodies are removed, through the interaction with Th2-type cytokines (i.e. IL-4), macrophages become anti-inflammatory and repair damaged tissues. Incubation of bone-marrow-derived macrophages with IFN-gamma or IL-4 blocked their proliferation. While M-CSF withdrawal caused cell cycle arrest at the early G(1) phase, treatment of macrophages with IFN-gamma or IL-4 caused this arrest later, at the G(1)/S boundary. Proliferation arrest was not due to an induction of apoptosis. IFN-gamma and IL-4 induced the expression of the cyclin-dependent kinase (Cdk) inhibitor p21(Waf1). Using KO mice and iRNA experiments, we found that p21(Waf1)is required for IL-4- but not for IFN-gamma-dependent inhibition of macrophage proliferation. IL-4 inhibited M-CSF-dependent Cdk-2 and Cdk-4 activities, which are necessary for entry and passage through the S phase of the cell cycle. The signal transduction used to induce the expression of p21(Waf1)after interaction of IL-4 with the corresponding receptor was mediated by STAT6. Thus, IL-4 and IFN-gamma blocked M-CSF-induced macrophage proliferation through distinct mechanisms.

CDK inhibitor

10.1002/eji.200838283

Cite

Citations (38)

Arginine Transport via Cationic Amino Acid Transporter 2 Plays a Critical Regulatory Role in Classical or Alternative Activation of Macrophages

The Journal of Immunology (2006)

Andrée Yeramian Lorena Martín‐Jaular Neus Serrat Luís Arpa Concepció Soler

Abstract Arginine is processed by macrophages in response to the cytokines to which these cells are exposed. Th1-type cytokines induce NO synthase 2, which metabolizes arginine into nitrites, while the Th2-type cytokines produce arginase, which converts arginine into polyamines and proline. Activation of bone marrow-derived macrophages by these two types of cytokines increases l-arginine transport only through the y+ system. Analysis of the expression of the genes involved in this system showed that Slc7A1, encoding cationic amino acid transporters (CAT)1, is constitutively expressed and is not modified by activating agents, while Slc7A2, encoding CAT2, is induced during both classical and alternative activation. Macrophages from Slc7A2 knockout mice showed a decrease in l-arginine transport in response to the two kinds of cytokines. However, while NO synthase 2 and arginase expression were unmodified in these cells, the catabolism of arginine was impaired by both pathways, producing smaller amounts of nitrites and also of polyamines and proline. In addition, the induction of Slc7A2 expression was independent of the arginine available and of the enzymes that metabolize it. In conclusion, the increased arginine transport mediated by activators is strongly regulated by CAT2 expression, which could limit the function of macrophages.

Amino acid transporter

Catabolism

10.4049/jimmunol.176.10.5918

Cite

Citations (132)