Activities of Chemokines in Vivo

Farber, J.

Abstract

The goal of the project is to investigate the biological roles of members of the chemokine family of cytokines by studying chemokine actions in vivo, primarily in animal models of infectious disease. Through differential screening of a cDNA library prepared from lymphokine-activated macrophages, this laboratory discovered two mouse chemokines, Crg-2 and Mig. Crg-2 is likely the mouse homologue of the human chemokine IP-10, and the murine Mig (MuMig) was used to identify a human homologue, HuMig. Crg-2/IP-10 and Mig are relate, interferon- gamma inducible chemokines that preferentially target T lymphocytes, acting as chemotactic factors for activated T cells. Following injection of mice with interferon-gamma, mig was induced dramatically in multiple organs. In analyses of animal models infectious disease, infection of mice with the malarial parasite P. Yoellii induced mig in liver, spleen, lung and heart. Infection of mice with the protozoa T, gondii led to induction of mig early after infection in liver, lung, spleen and heart and at later times in brain. Infection of mice with vaccinia virus induced mig in liver, ovary, uterus, spleen, heart and lung. Using interferon-gamma knockout mice or anti-interferon- gamma antibodies, wee demonstrated that inductions of mig by infection with T. gondii and vaccinia virus were dependent absolutely on interferon gamma. Expression of Crg-2/PI-10 of these models was similar to that of mig, but with notable exceptions. We presume that Mig and Crg-2/IP-10 are mediating interferon-gamma dependent effects on the trafficking of activated T cells and that Mig's and Crg-2/IP-10's activities are important for host defense against a variety of pathogens. Ongoing work is concentrating on more precise localization of expression of mig and other chemokines in tissues and cells in the animal systems and on experiments to determine the biological roles for the chemokines in these systems, including the production of mice with targeted deletion of the mig gene.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Allergy and Infectious Diseases (NIAID)
• Type: Intramural Research (Z01)
• Project #: 1Z01AI000725-01
• Application #: 5200609
• Support Year: 1
• Fiscal Year: 1995

Institution

• Name: National Institute of Allergy and Infectious Diseases
• Country: United States

Publications

Hedrick, Michael N; Lonsdorf, Anke S; Shirakawa, Aiko-Konno et al. (2009) CCR6 is required for IL-23-induced psoriasis-like inflammation in mice. J Clin Invest 119:2317-29

Cortes, Lizette M; Mattapallil, Mary J; Silver, Phyllis B et al. (2008) Repertoire analysis and new pathogenic epitopes of IRBP in C57BL/6 (H-2b) and B10.RIII (H-2r) mice. Invest Ophthalmol Vis Sci 49:1946-56

Gorbachev, Anton V; Kobayashi, Hirohito; Kudo, Daisuke et al. (2007) CXC chemokine ligand 9/monokine induced by IFN-gamma production by tumor cells is critical for T cell-mediated suppression of cutaneous tumors. J Immunol 178:2278-86

Barlic, Jana; Zhang, Yuan; Foley, John F et al. (2006) Oxidized lipid-driven chemokine receptor switch, CCR2 to CX3CR1, mediates adhesion of human macrophages to coronary artery smooth muscle cells through a peroxisome proliferator-activated receptor gamma-dependent pathway. Circulation 114:807-19

Wuest, Todd; Farber, Joshua; Luster, Andrew et al. (2006) CD4+ T cell migration into the cornea is reduced in CXCL9 deficient but not CXCL10 deficient mice following herpes simplex virus type 1 infection. Cell Immunol 243:83-9

Wald, Ori; Weiss, Ido D; Wald, Hanna et al. (2006) IFN-gamma acts on T cells to induce NK cell mobilization and accumulation in target organs. J Immunol 176:4716-29

Medoff, Benjamin D; Wain, John C; Seung, Edward et al. (2006) CXCR3 and its ligands in a murine model of obliterative bronchiolitis: regulation and function. J Immunol 176:7087-95

Fulkerson, Patricia C; Zimmermann, Nives; Brandt, Eric B et al. (2004) Negative regulation of eosinophil recruitment to the lung by the chemokine monokine induced by IFN-gamma (Mig, CXCL9). Proc Natl Acad Sci U S A 101:1987-92

Park, Matthew K; Amichay, Doron; Love, Paul et al. (2002) The CXC chemokine murine monokine induced by IFN-gamma (CXC chemokine ligand 9) is made by APCs, targets lymphocytes including activated B cells, and supports antibody responses to a bacterial pathogen in vivo. J Immunol 169:1433-43

Uehara, Shoji; Song, Kaimei; Farber, Joshua M et al. (2002) Characterization of CCR9 expression and CCL25/thymus-expressed chemokine responsiveness during T cell development: CD3(high)CD69+ thymocytes and gammadeltaTCR+ thymocytes preferentially respond to CCL25. J Immunol 168:134-42