TY - JOUR
T1 - Pro- and Antiinflammatory Cytokine Signaling
T2 - Reciprocal Antagonism Regulates Interferon-gamma Production by Human Natural Killer Cells
AU - Yu, Jianhua
AU - Wei, Min
AU - Becknell, Brian
AU - Trotta, Rossana
AU - Liu, Shujun
AU - Boyd, Zachary
AU - Jaung, Michael S.
AU - Blaser, Bradley W.
AU - Sun, Jin
AU - Benson, Don M.
AU - Mao, Hsiaoyin
AU - Yokohama, Akihiko
AU - Bhatt, Darshna
AU - Shen, Lei
AU - Davuluri, Ramana
AU - Weinstein, Michael
AU - Marcucci, Guido
AU - Caligiuri, Michael A.
N1 - Funding Information:
We thank Tiffany Hughes, Trent Marburger, Hua Li, Weifeng Yuang, Wei Ding, Jeffrey Allard II, Ye Liu, and Ben Scheier for technical assistance and Aharon Freud for purifying primary human NK cells. This work was supported by The Real Time RT-PCR and The Nucleic Acid Shared Resources within The Ohio State University Comprehensive Cancer Center and by National Cancer Institute grants (CA95426 and CA68458 to M.A.C.). J.Y. was supported by the Up on the Roof Fellowship from the Division of Human Cancer Genetics at The Ohio State University.
PY - 2006/5
Y1 - 2006/5
N2 - Activated monocytes produce proinflammatory cytokines (monokines) such as interleukin (IL)-12, IL-15, and IL-18 for induction of interferon-γ (IFN-γ) by natural killer (NK) cells. NK cells provide the antiinflammatory cytokine transforming growth factor (TGF)-β, an autocrine/negative regulator of IFN-γ. The ability of one signaling pathway to prevail over the other is likely important in controlling IFN-γ for the purposes of infection and autoimmunity, but the molecular mechanism(s) of how this counterregulation occurs is unknown. Here we show that in isolated human NK cells, proinflammatory monokines antagonize antiinflammatory TGF-β signaling by downregulating the expression of the TGF-β type II receptor, and its signaling intermediates SMAD2 and SMAD3. In contrast, TGF-β utilizes SMAD2, SMAD3, and SMAD4 to suppress IFN-γ and T-BET, a positive regulator of IFN-γ. Indeed, activated NK cells from Smad3-/- mice produce more IFN-γ in vivo than NK cells from wild-type mice. Collectively, our data suggest that pro- and antiinflammatory cytokine signaling reciprocally antagonize each other in an effort to prevail in the regulation of NK cell IFN-γ production.
AB - Activated monocytes produce proinflammatory cytokines (monokines) such as interleukin (IL)-12, IL-15, and IL-18 for induction of interferon-γ (IFN-γ) by natural killer (NK) cells. NK cells provide the antiinflammatory cytokine transforming growth factor (TGF)-β, an autocrine/negative regulator of IFN-γ. The ability of one signaling pathway to prevail over the other is likely important in controlling IFN-γ for the purposes of infection and autoimmunity, but the molecular mechanism(s) of how this counterregulation occurs is unknown. Here we show that in isolated human NK cells, proinflammatory monokines antagonize antiinflammatory TGF-β signaling by downregulating the expression of the TGF-β type II receptor, and its signaling intermediates SMAD2 and SMAD3. In contrast, TGF-β utilizes SMAD2, SMAD3, and SMAD4 to suppress IFN-γ and T-BET, a positive regulator of IFN-γ. Indeed, activated NK cells from Smad3-/- mice produce more IFN-γ in vivo than NK cells from wild-type mice. Collectively, our data suggest that pro- and antiinflammatory cytokine signaling reciprocally antagonize each other in an effort to prevail in the regulation of NK cell IFN-γ production.
KW - CELLIMMUNO
KW - MOLIMMUNO
UR - http://www.scopus.com/inward/record.url?scp=33646563695&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33646563695&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2006.03.016
DO - 10.1016/j.immuni.2006.03.016
M3 - Article
C2 - 16713975
AN - SCOPUS:33646563695
SN - 1074-7613
VL - 24
SP - 575
EP - 590
JO - Immunity
JF - Immunity
IS - 5
ER -
