Novel Cytokines From Activated Macrophages

Farber, Joshua M.

Abstract

The overall goal of the project has been to identify and characterize the function of macrophage products of potential importance in immune and inflammatory responses in order to manipulate these responses for clinical benefit. This laboratory identified mouse and human Mig and mouse Crg-2/IP-10, previously undescribed members of a family of small secreted proteins, termed chemokines. Mig and Crg-2/IP-10 are inducible in macrophage and other cells by IFN-gamma and target activated T cells, B cells and NK cells through the CXCR3 receptor, which they share with I-TAC, another interferon-inducible chemokine. Work in the last year has focused on novel findings for the expression of Crg-2/IP-10, and to a lesser extent Mig in liver disease in humans, and in mouse models of liver and bile duct injury and regeneration. The pattern of Crg-2/IP-10 induction suggests both that Crg-2/IP-10 is part of a systemic response to injury and that Crg-2/IP-10 has a role in liver regeneration. In addition, we have been investigating possible roles for Crg-2/IP-10 and I-TAC in HIV/AIDS, related to the co-expression of CXCR3 and the major HIV coreceptor, CCR5, on CD4+ memory T cells. Our findings suggest that the recruitment of CCR5+ memory/effector T cells by CXCR3 ligands may contribute to the dissemination of HIV infection.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Allergy and Infectious Diseases (NIAID)
• Type: Intramural Research (Z01)
• Project #: 1Z01AI000680-09
• Application #: 6514011
• Study Section: (LCI)
• Support Year: 9
• Fiscal Year: 2001

Institution

• Name: Niaid Extramural Activities
• Country: United States

Publications

Foley, John F; Yu, Cheng-Rong; Solow, Rikki et al. (2005) Roles for CXC chemokine ligands 10 and 11 in recruiting CD4+ T cells to HIV-1-infected monocyte-derived macrophages, dendritic cells, and lymph nodes. J Immunol 174:4892-900

Song, Kaimei; Rabin, Ronald L; Hill, Brenna J et al. (2005) Characterization of subsets of CD4+ memory T cells reveals early branched pathways of T cell differentiation in humans. Proc Natl Acad Sci U S A 102:7916-21

Koniaris, L G; Zimmers-Koniaris, T; Hsiao, E C et al. (2001) Cytokine-responsive gene-2/IFN-inducible protein-10 expression in multiple models of liver and bile duct injury suggests a role in tissue regeneration. J Immunol 167:399-406

Arthos, J; Rubbert, A; Rabin, R L et al. (2000) CCR5 signal transduction in macrophages by human immunodeficiency virus and simian immunodeficiency virus envelopes. J Virol 74:6418-24

Yu, C R; Peden, K W; Zaitseva, M B et al. (2000) CCR9A and CCR9B: two receptors for the chemokine CCL25/TECK/Ck beta-15 that differ in their sensitivities to ligand. J Immunol 164:1293-305

Peden, K W; Farber, J M (2000) Coreceptors for human immunodeficiency virus and simian immunodeficiency virus. Adv Pharmacol 48:409-78

Sommers, C L; Rabin, R L; Grinberg, A et al. (1999) A role for the Tec family tyrosine kinase Txk in T cell activation and thymocyte selection. J Exp Med 190:1427-38

Liao, F; Rabin, R L; Smith, C S et al. (1999) CC-chemokine receptor 6 is expressed on diverse memory subsets of T cells and determines responsiveness to macrophage inflammatory protein 3 alpha. J Immunol 162:186-94

Gasperini, S; Marchi, M; Calzetti, F et al. (1999) Gene expression and production of the monokine induced by IFN-gamma (MIG), IFN-inducible T cell alpha chemoattractant (I-TAC), and IFN-gamma-inducible protein-10 (IP-10) chemokines by human neutrophils. J Immunol 162:4928-37

Rabin, R L; Park, M K; Liao, F et al. (1999) Chemokine receptor responses on T cells are achieved through regulation of both receptor expression and signaling. J Immunol 162:3840-50