Thursday, 23rd January 2020

Regulation and function of proinflammatory mediators and their involvement in immune and inflammatory mediated diseases






Manuel Fresno









Research summary:

Atheroma formation is increased in mice  with a selective Cox-2 deficiency .  Irradiated ApoE-/- mice were reconstituted with Bone Marrow from Wild type (WT) or Cox-2 -/-  mice. 12 weeks after being on a high-fat-diet, arteries were analyzed.
Arginase I and CD68 expression in BALB/c mice heart tissue during acute T. cruzi infection. Tissue sections obtained from hearts of infected BALB/c mice analysed by immunofluorescence confocal microscopy. Boxed regions are shown at two-fold magnification of original (x400) in insets.

Inflammation underlies many of the most prevalent diseases of the developed countries, as Cardiovascular diseases, Obesity and Cancer. We focused on molecular mechanisms of inflammation and induction and activity of inflammatory mediators. We demonstrated the early induction of Cox-2 in T lymphocytes after TCR triggering, having this molecule important functional effects on T cell activity and demonstrated the crucial role of NFAT/Cox-2 in endothelial and colon carcinoma cells. We also demonstrated that c-rel activity can be modulated through phosphorylation, subsequently extended to NFAT, defining a new signal transduction pathway involving NIK, Cot and PK- Cz  kinases.

There are similarities between recognition of pathogens by TLR, the immune response induced for infection and chronic inflammation.Our current work is based in the involvement of TLR/NIK/c-rel-NFAT/Cox-2/prostaglandins (PGs) in novel functions of the immune system and in inflammatory pathologies as Atherosclerosis, Obesity Cancer and GVHD. We are using a multidisciplinary approach (Cell and Molecular Biology, Immunology and integrated imaging techniques) and murine models of disease. We are analyzing the regulation and function of TLR/NIK/c-rel-NFAT/Cox-2/PGs in various tissues and cell types and addressing the cellular interactions and the signal transduction pathways triggered by PGs, chemokines and cytokines and their mutual influence in various cell types and in animal models.

We have started to unravel the link between TLRs and some of their signaling pathways that activate c-rel and NFAT. Moreover, c-rel and NFAT through the control of some important mediators of the inflammatory cascade, as Cox-2, increase inflammatory responses. Besides, PGs trigger migration of immune cells and affect the cardiovascular system, adipogenesis and cancer. We have also found that TLR2/NFAT axis controls the expression of some adipogenic genes and repressed the antiadipogenic ones.

On the other hand, Trypanosoma cruzi, the agent of Chagas’disease, is a heterogeneous complex of organisms. Genetic lineages have been defined, however, understanding of their comparative biology and public health importance is fragmentary. Besides, the underlying cause of the pathogenesis of this disease (autoimmunity vs parasite mediated inflammation) is controversial.  We have contributed in the past, to define the protective immune mechanism and recently to the double-edge role of NO and myeloid derived suppressor cells (MDSC) and other immunopathogenic mechanisms. Our current focus is to continue the elucidation of  the pathogenic mechanism underlying T. cruzi infection (and by extension to other related infections) specially the contribution of Th17, Tregs or MDSC responses and autoimmunity as well as the pathogenetic differences between genetic lineages of T. cruzi. Besides, we are studying how the parasite enters, infects and escapes destruction by myeloid cells. All intended for improved understanding and prevention of Chagas’disease.  



  • Aquilino, C., Gonzalez Rubio, M.L., Seco, E.M., Escudero, L., Corvo, L., Soto, M., Fresno, M., Malpartida, F., and Bonay, P. (2012). Differential trypanocidal activity of novel macrolide antibiotics; correlation to genetic lineage. PLoS One 7, e40901.
  • Calderon, J., Maganto-Garcia, E., Punzon, C., Carrion, J., Terhorst, C., and Fresno, M. (2012). The Receptor Slamf1 on the Surface of Myeloid Lineage Cells Controls Susceptibility to Infection by Trypanosoma cruzi. PLoS Pathog. 8, e1002799.
  • Calvo-Alvarez, E., Guerrero, N.A., Alvarez-Velilla, R., Prada, C.F., Requena, J.M., Punzon, C., Llamas, M.A., Arevalo, F.J., Rivas, L., Fresno, M., Perez-Pertejo, Y., Balana-Fouce, R., and Reguera, R.M. (2012). Appraisal of a Leishmania major strain stably expressing mCherry fluorescent protein for both in vitro and in vivo studies of potential drugs and vaccine against cutaneous leishmaniasis. PLoS Negl. Trop. Dis. 6, e1927.
  • De La Fuente, H., Perez-Gala, S., Bonay, P., Cruz-Adalia, A., Cibrian, D., Sanchez-Cuellar, S., Dauden, E., Fresno, M., Garcia-Diez, A., and Sanchez-Madrid, F. (2012). Psoriasis in humans is associated with down-regulation of galectins in dendritic cells. J. Pathol. 228, 193-203.
  • Diaz-Munoz, M.D., Osma-Garcia, I.C., Fresno, M., and Iniguez, M.A. (2012). Involvement of PGE2 and the cAMP signalling pathway in the up-regulation of COX-2 and mPGES-1 expression in LPS-activated macrophages. Biochem. J. 443, 451-461.


Other activities:

Socio Honorario Sociedad Cubana de Inmunología. Mayo, 2012.



Sánchez López, José Mª, Martínez Insua, Marta, Romero Millán, Francisco, FERNÁNDEZ-MEDARDE, Antonio, FERNÁNDEZ CHIMENO, Rosa Isabel, FRESNO ESCUDERO, Manuel, SÁNCHEZ VALDEPEÑAS, María del Carmen, RAMÍREZ ORELLANA, Manuel. HEXACYCLIC POLYKETIDES AS KINASE INHIBITORS. N. de solicitud: PCT/EP2011/062379 Fecha de prioridad: 19.07.2011 Entidad titular: INSTITUTO BIOMAR, S.A. Empresa/s que la están explotando: INSTITUTO BIOMAR, S.A.


Doctoral theses:

Vinatha Sreeramjumar (2011). Role of Prostaglandin E2 in T cell activation and migration. Universidad Autónoma de Madrid. Convenio de Cotuela UAM-Universidad de San Raffelle (Roma, Italia). Director: Manuel Fresno. Co-directores: Dr. Federico Mayor Menéndez y Dra. Natalia Cuesta.

Jossela Calderón Deago (2011). Implicación del receptor SLAM (CD150) en la infección por Trypanosoma cruzi.Universidad Autónoma de Madrid. Director: Manuel Fresno.

Inés Claire García Osma (2012). Prostaglandinas dependientes de ciclooxigenasa-2<: Moléculas clave en el conrol funcional de los macrófagos. Universidad Autónoma de Madrid. Director: Manuel Fresno.

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