Macrophage biology: regulation of gene expression
Antonio Celada
Principal Investigator
Professor of Immunology (Physiology Dept. - UB)
Office Tel : +34 93 403 71 65
Lab Tel : +34 93 403 71 64
e-mail : antonio.celada
irbbarcelona.org
Background
Macrophages are produced in the bone marrow and are located in all the organs of the body, where they differentiate and become microglia (brain), Kupffer cells (liver), Langerhans cells (skin), dendritic cells, among others. Macrophages are critical in the immune system as they directly phagocytize and destroy bacteria, fungi, parasites and virus. They also release a large number of molecules that regulate the function of other cells. For example, they produce TNF-α or IL-1, which are responsible for the production of fever. They also present the antigens processed as peptides to T lymphocytes, an obligatory step to produce immunological memory, the basis for vaccine activity. Macrophages not only destroy micro-organisms but also play a key role in wound healing, tissue repair and vascularization. Finally, these cells have important functions outside of the immune system, such as the control of iron or lipid metabolisms. The dendritic cells that derive from macrophages are potent antigen-presenting cells and at the present are used in clinical trials to induce immunity against tumors or to remove the HIV virus from infected patients under treatment.
Research Interests
Our research involves the use of genomics and proteomics tools to study the molecular mechanisms involved in macrophage proliferation, activation, differentiation and entry in apoptosis following stimulation with cytokines or growth factors. We aim to determine the signal transduction pathways for macrophages and to establish how the various genes involved in the functional activity of these cells are regulated. Given that the major histocompatibility complex class II genes are critical for antigen presentation to T lymphocytes, we address the regulation of the expression of these genes. We also study gene dysregulation in macrophage immunosenescence.
Research Lines
Regulation of genes that determine the proliferation, differentiation, activation and apoptosis of macrophages.
We study the first steps of signal transduction that either determine macrophage proliferation or activation. A particular focus is on the regulation of MAP kinases and the corresponding phosphatases. We also examine the processes of classical and alternative activation of macrophages and in particular the role of arginase. For classical activation, we address the regulation of MHC class II genes.
Aging and dysregulation of gene expresion in the immune system.
We have found that aged mice lack a protein that mediates signalling for proliferation, differentiation and protection from apoptosis. We aim to identify the mechanisms that inhibit the expression of this protein and to determine the role of telomers in macrophage aging and also that of several proteins involved in DNA repair.
Roles of the nuclear receptor LXR in macrophage biology.
Nuclear receptors are members of a superfamily of ligand-dependent transcription factors that regulate diverse aspects of development and homeostasis. LXRs upregulate the expression of genes involved in lipid metabolism. Apart from their role in lipid homeostasis, LXRs inhibit the expression of proinflammatory genes through a mechanism of transrepression. Moreover, LXRs upregulate antiapoptotic genes and protect macrophages from programmed cell death associated to bacterial infection. Our goal is to study transcriptional programs that are regulated by LXRs in immune cells and to continue exploring the physiologic effects that LXR agonists exert in innate and acquired immunity.
This line of research is carried out by Dr. Annabel Fernandez Valledor.
Funding
This group receives financial supprot from the following sources:
- Ministerio de Educación y Ciencia (Spanish Ministry of Science and Education)
- European Commission (FP6)
More info
Macrophage biology: regulation of gene expression
Macrophage activation: classical versus alternative
Classen A, Lloberas J and Celada A
Methods Mol Biol. Humana Press, Macrophages and Dendritic Cells Volume, Reiner N (Ed.) (In press) (2009)
The MKP-1 expression is regulated in macrophages by M-CSF or LPS through a CREB/AP-1 box
Casals C, Alvarez E, Serra M, de la Torre C, Sánchez-Tilló E, Lloberas J and Celada A
J Immunol (In press) (2009)
Molecular and cellular aspects of macrophAging
Sebastián C, Lloberas J and Celada A
Handbook on Immunosenescence: basic understanding and clinical applications. Fulop T, Franceschi C, Hirokawa, K Pawelec, G (Eds.), Springer (In press) (2009)
The kinase p38 alpha serves cell type-specific inflammatory functions in skin injury and coordinates pro- and anti-inflammatory gene expression
Kim C, Sano Y, Todorova K, Carlson B, Arpa L, Celada A, Lawrence T, Otsu K, Brissette J, Arthur JC and Park JM
Nat Immunol, 9 (9), 1019-1027 (2008)
IFN-γ-mediated inhibition of MAPK phosphatase expression results in prolonged MAPK activity in response to M-CSF and inhibition of proliferation
Valledor AF, Arpa L, Sanchez-Tillo E, Comalada M, Casals C, Xaus J, Caelles C, Lloberas J and Celada A
Blood, 112 (8), 3274-3282 (2008)
Granulocyte macrophage-colony-stimulating factor-dependent proliferation is impaired in macrophages from senescence-accelerated mice
Espía M, Sebastian C, Mulero M, Giralt M, Mallol J, Celada A and Lloberas J
J Gerontol A Biol Sci Med Sci, 63 (11), 1161-1167 (2008)
Deacetylase activity is required for STAT5-dependent GM-CSF functional activity in macrophages and differentiation to dendritic cells
Sebastian C, Serra M, Yeramian A, Serrat N, Lloberas J and Celada A
J Immunol, 180 (9), 5898-5906 (2008)
Autoregulation mechanism of human neutrophil apoptosis during bacterial infection
Ocaña MG, Asensi V, Montes AH, Meana A, Celada A and Valle-Garay E
Mol Immunol, 45 (7), 2087-2096 (2008)
Selective roles of MAPKs during the macrophage response to IFN-gamma
Valledor AF, Sánchez-Tilló E, Arpa L, Park JM, Caelles C, Lloberas J and Celada A
J Immunol, 180 (7), 4523-4529 (2008)
Structural and biochemical studies of TREX1 inhibition by metals. Identification of a new active histidine conserved in DEDDh exonucleases
Brucet M, Querol-Audí J, Bertlik K, Lloberas J, Fita I and Celada A
Protein Sci, 17 (12), 2059-2069 (2008)
IL-4 blocks M-CSF-dependent macrophage proliferation by inducing p21Waf1 in a Stat6-dependent way
Valledor AF, Lloberas J and Celada A
J Immunol (In press) (2008)
Peptides conjugated to gold nanoparticles induce macrophage activation
Bastús NG, Sánchez-Tilló E, Pujals S, Farrera C, Kogan MJ, Giralt E, Celada A, Lloberas J and Puntes V
Mol Immunol (In press) (2008)
Structure of the dimeric exonuclease TREX1 in complex with DNA displays a proline-rich binding site for WW Domains
Brucet M, Querol-Audí J, Serra M, Ramirez-Espain X, Bertlik K, Ruiz L, Lloberas J, Macias MJ, Fita I and Celada A
J Biol Chem, 282 (19), 14547-14557 (2007)
Lipopolysaccharide up-regulates MHC class II expression on dendritic cells through an AP-1 enhancer without affecting the levels of CIITA
Casals C, Barrachina M, Serra M, Lloberas J and Celada A
J Immunol, 178 (10), 6307-6315 (2007)
Kv1.3/Kv1.5 heteromeric channels compromise pharmacological responses in macrophages
Villalonga N, Escalada A, Vicente R, Sanchez-Tillo E, Celada A, Solsona C and Felipe A
Biochem Biophys Res Commun, 352 (4), 913-918 (2007)
The NOS3 (27-bp repeat, intron 4) polymorphism is associated with susceptibility to osteomyelitis
Asensi V, Montes AH, Valle E, Ocaña MG, Astudillo A, Alvarez V, Lopez-Anglada E, Solis A, Coto E, Meana A, Gonzalez P, Cartón JA, Paz J, Fierer J and Celada A
Nitric Oxide, 16 (1), 44-53 (2007)
JNK1 is required for the induction of Mkp1 expression in macrophages during proliferation and lipopolysaccharide-dependent activation
Sanchez-Tillo E, Comalada M, Xaus J, Farrera C, Valledor AF, Caelles C, Lloberas J and Celada A
J Biol Chem, 282 (17), 12566-12573 (2007)
Bax gene G(-248)A promoter polymorphism is associated with increased lifespan of the neutrophils with osteomyelitis
Ocaña MG, Valle-Garay E, Montes AH, Meana A, Carton JA, Fierer J, Celada A and Asensi V
Genet Med, 9 (4), 249-255 (2007)
NMR structural studies of the ItchWW3 domain reveal that phosphorylation at T30 inhibits the interaction with PPxY-containing ligands
Morales B, Ramirez-Espain X, Shaw AZ, Martin-Malpartida P, Yraola F, Sánchez-Tilló E, Farrera C, Celada A, Royo M and Macias MJ
Structure, 15 (4), 473-483 (2007)
Lipopolysaccharide up-regulates MHC class II expression on dendritic cells through an AP-1 enhacer without affecting the levels of CIITA
Casals C, Barrachina M, Serra M, Lloberas J, and Celada A
J Immunol, 178 (10), 6307-6315 (2007)
Cyclophilin A is required for M-CSF-dependent macrophage proliferation
Sànchez-Tilló E, Wojciechowska M, Comalada M, Farrera C, Lloberas J and Celada A
Eur J Immunol, 36 (9), 2515-2524 (2006)
Arginine transport via cationic amino acid transporter 2 plays a critical regulatory role in classical or alternative activation of macrophages
Yeramian A, Martín L, Serrat N, Arpa L, Soler C, Bertran J, McLeod C, Palacín M, Modolell M, Lloberas J and Celada A
J Immunol, 176 (10), 5918-5924 (2006)
Granulocyte-macrophage colony-stimulating factor increases L-arginine transport through the induction of CAT2 in bone marrow-derived macrophages
Martin L, Comalada M, Marti L, Closs EI, Macleod CL, Martin Del Rio R, Zorzano A, Modolell M, Celada A, Palacin M and Bertran J
Am J Physiol Cell Physiol, 290 (5), C1364-1372 (2006)
The Toll-like receptor 4 (Asp299Gly) polymorphism is a risk factor for Gram-negative and haematogenous osteomyelitis
Asensi V, Montes AH, Alvarez V, Valle E, Ocaña MG, Meana A, Carton JA, Paz J, Fierer J and Celada A
Clin Exp Immunol, 143 (3), 404-413 (2006)
Macrophages require distinct arginine catabolism and transport systems for proliferation and for activation
Yeramian A, Martin L, Arpa L, Bertran J, Soler C, McLeod C, Modolell M, Palacin M, Lloberas J and Celada A
Eur J Immunol, 36 (6), 1516-1526 (2006)
Macrophage-colony-stimulating factor-induced proliferation and lipopolysaccharide-dependent activation of macrophages requires Raf-1 phosphorylation to induce mitogen kinase phosphatase-1 expression
Sánchez-Tilló E, Comalada M, Farrera C, Valledor AF, Lloberas J and Celada A
J Immunol, 176 (11), 6594-6602 (2006)
Arginase and polyamines synthesis are key factors in the regulation of experimental leishmaniasis in vivo
Kropf P, Fuentes JM, Fähnrich E, Arpa L, Herath S, Weber V, Soler G, Celada A, Modolell M, and Müller I
FASEB J, 19 (8), 1000-1002 (2005)
Pattern of Kv beta subunit expression in macrophages depends upon proliferation and the mode of activation
Vicente R, Escalada A, Soler C, Grande M, Celada A, Tamkun MM, Solsona C and Felipe A
J Immunol, 174 (8), 4736-4744 (2005)
The innate immune response under the control of the LXR pathway
Valledor AF
Immunobiology, 210 (2-4), 127-132 (2005)
MacrophAging: a cellular and molecular review
Sebastián C, Espia M, Serra M, Celada A and Lloberas J
Immunobiology, 210 (2-4), 121-126 (2005)
STAT1 regulates lipopolysaccharide- and TNF-alpha-dependent expression of transporter associated with antigen processing 1 and low molecular mass polypeptide 2 genes in macrophages by distinct mechanisms
Marqués L, Brucet M, Lloberas J and Celada A
J Immunol, 173 (2), 1103-1110 (2004)
In vivo interleukin-6 protects neutrophils from apoptosis in osteomyelitis
Asensi V, Valle E, Meana A, Fierer J, Celada A, Alvarez V, Paz J, Coto E, Carton JA, Maradona JA, Dieguez A, Sarasúa J, Ocaña MG and Arribas JM
Infect Immun, 72 (7), 3823-3828 (2004)
Regulation of murine TAP1 and LMP2 genes in macrophages by interferon gamma is mediated by Stat1 and IRF-1
Brucet M, Marqués L, Sebastian C, Lloberas J and Celada A
Genes Immun, 5 (1), 26-35 (2004)
Expression of the nucleoside-derived drug transporters hCNT1, hENT1 and hENT2 in gynecologic tumors
Farre X, Guillen-Gomez E, Sanchez L, Hardisson D, Plaza Y, Lloberas J, Casado FJ, Palacios J and Pastor-Anglada M
Int J Cancer, 112 (6), 959-966 (2004)
Macrophage colony-stimulating factor-, granulocyte-macrophage colony-stimulating factor-, or IL-3-dependent survival of macrophages, but not proliferation, requires the expression of p21(Waf1) through the phosphatidylinositol 3-kinase/Akt pathway
Comalada M, Xaus J, Sanchez E, Valledor AF and Celada A
Eur J Immunol, 34 (8), 2257-2267 (2004)
Interferon-gamma regulates nucleoside transport systems in macrophages through signal transduction and activator of transduction factor 1 (STAT1)-dependent and -independent signalling pathways
Soler C, Felipe A, García-Manteiga J, Serra M, Guillén-Gómez E, Casado FJ, MacLeod C, Modolell M, Pastor-Anglada M and Celada A
Biochem J, 375 (Pt 3), 777-783 (2003)
Macrophage colony-stimulating factor-dependent macrophage proliferation is mediated through a calcineurin-independent but immunophilin-dependent mechanism that mediates the activation of external regulated kinases
Comalada M, Valledor AF, Umbert I, Xaus J and Celada A
Eur J Immunol, 33 (11), 3091-3100 (2003)
Differential voltage-dependent K+ channel responses during proliferation and activation in macrophages
Vicente R, Escalada A, Coma M, Fuster G, Lopez-Iglesias C, Soler C, Solsona C, Celada A and Felipe A
J Biol Chem, 278 (47), 46307-46320 (2003)
PKC is involved in JNK activation that mediates LPS-induced TNF, which induces apoptosis in macrophages
Comalada M, Xaus J, Valledor AF, López-López C, Pennington DJ and Celada A
Am J Physiol Cell Physiol, 285 (5), C1235-C1245 (2003)
Decorin reverses the repressive effect of the autocrine-produced TGF on mouse macrophage activation
Comalada M, Cardó M, Xaus J, Valledor AF, Lloberas J, Ventura F and Celada A
J Immunol, 170 (9), 4450-4456 (2003)
High expression of p21 Waf1 in sarcoid granulomas: a putative role for long-lasting inflammation
Xaus J, Besalduch N, Comalada M, Marcoval J, Pujol R, Mañá J and Celada A
J Leukoc Biol, 74 (2), 295-301 (2003)
