Molecular mechanism(s) involved in the synergistic induction of CXCL10 by human immunodeficiency virus type 1 Tat and interferon-gamma in macrophages.
Synergistic interactions between viral proteins and soluble host factors released from infected mononuclear phagocytes play a critical role in the pathogenesis of human immunodeficiency virus (HIV)-associated dementia (HAD). The chemokine CXCL10 has been found to be closely associated with the progression of HIV-1-related central nervous system (CNS) disease and its related neuropsychiatric impairment. In this report the authors demonstrate that the HIV-1 protein Tat can interact with the proinflammatory cytokine interferon (IFN)-gamma to dramatically induce the expression of CXCL10 in macrophages. Synergistic induction of CXCL10 by both Tat and IFN-gamma was susceptible to inhibition by the MEK1/2 inhibitor U0126 and the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580. In addition, JAK/STAT pathway plays a major role in Tat/gamma-mediated CXCL10 induction in macrophages because pretreatment of stimulated macrophages with JAK inhibitor completely abrogated the synergistic induction of the chemokine. Functionality of the synergistically induced CXCL10 was further demonstrated by its chemotactic activity for peripheral blood lymphocytes. Taken together, these findings demonstrate that the cooperative interaction of Tat and IFN-gamma results in enhanced chemokine expression, which in turn can amplify the inflammatory responses within the CNS of HAD patients by recruiting more lymphocytes in the brain.
Dhillon
Navneet
N
Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
Zhu
Xuhui
X
Peng
Fuwang
F
Yao
Honghong
H
Williams
Rachel
R
Qiu
Jianming
J
Callen
Shannon
S
Ladner
Amy O'Brien
AO
Buch
Shilpa
S
D015526:AIDS Dementia Complex / Q000276:immunology / Q000821:virology; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D053612:Janus Kinases / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
D054357:Chemokine CXCL10; D050791:STAT Transcription Factors; D054322:tat Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma; D053612:Janus Kinases; D020928:Mitogen-Activated Protein Kinases