Pro- and Antiinflammatory Cytokine Signaling: Reciprocal Antagonism Regulates Interferon-gamma Production by Human Natural Killer Cells

Jianhua Yu; Min Wei; Brian Becknell; Rossana Trotta; Shujun Liu; Zachary Boyd; Michael S. Jaung; Bradley W. Blaser; Jin Sun; Don M. Benson; Hsiaoyin Mao; Akihiko Yokohama; Darshna Bhatt; Lei Shen; Ramana Davuluri; Michael Weinstein; Guido Marcucci; Michael A. Caligiuri

doi:10.1016/j.immuni.2006.03.016

Pro- and Antiinflammatory Cytokine Signaling: Reciprocal Antagonism Regulates Interferon-gamma Production by Human Natural Killer Cells

Jianhua Yu, Min Wei, Brian Becknell, Rossana Trotta, Shujun Liu, Zachary Boyd, Michael S. Jaung, Bradley W. Blaser, Jin Sun, Don M. Benson, Hsiaoyin Mao, Akihiko Yokohama, Darshna Bhatt, Lei Shen, Ramana Davuluri, Michael Weinstein, Guido Marcucci, Michael A. Caligiuri

Research output: Contribution to journal › Article › peer-review

210 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	575-590
Number of pages	16
Journal	Immunity
Volume	24
Issue number	5
DOIs	https://doi.org/10.1016/j.immuni.2006.03.016
State	Published - May 2006
Externally published	Yes

Bibliographical note

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.

Keywords

CELLIMMUNO
MOLIMMUNO

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Yu, J., Wei, M., Becknell, B., Trotta, R., Liu, S., Boyd, Z., Jaung, M. S., Blaser, B. W., Sun, J., Benson, D. M., Mao, H., Yokohama, A., Bhatt, D., Shen, L., Davuluri, R., Weinstein, M., Marcucci, G., & Caligiuri, M. A. (2006). Pro- and Antiinflammatory Cytokine Signaling: Reciprocal Antagonism Regulates Interferon-gamma Production by Human Natural Killer Cells. Immunity, 24(5), 575-590. https://doi.org/10.1016/j.immuni.2006.03.016

Yu, J, Wei, M, Becknell, B, Trotta, R, Liu, S, Boyd, Z, Jaung, MS, Blaser, BW, Sun, J, Benson, DM, Mao, H, Yokohama, A, Bhatt, D, Shen, L, Davuluri, R, Weinstein, M, Marcucci, G & Caligiuri, MA 2006, 'Pro- and Antiinflammatory Cytokine Signaling: Reciprocal Antagonism Regulates Interferon-gamma Production by Human Natural Killer Cells', Immunity, vol. 24, no. 5, pp. 575-590. https://doi.org/10.1016/j.immuni.2006.03.016

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title = "Pro- and Antiinflammatory Cytokine Signaling: Reciprocal Antagonism Regulates Interferon-gamma Production by Human Natural Killer Cells",

abstract = "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.",

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author = "Jianhua Yu and Min Wei and Brian Becknell and Rossana Trotta and Shujun Liu and Zachary Boyd and Jaung, {Michael S.} and Blaser, {Bradley W.} and Jin Sun and Benson, {Don M.} and Hsiaoyin Mao and Akihiko Yokohama and Darshna Bhatt and Lei Shen and Ramana Davuluri and Michael Weinstein and Guido Marcucci and Caligiuri, {Michael A.}",

note = "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. ",

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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.

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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.

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Pro- and Antiinflammatory Cytokine Signaling: Reciprocal Antagonism Regulates Interferon-gamma Production by Human Natural Killer Cells

Abstract

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