Role of fatty-acid synthesis in dendritic cell generation and function

Adeel Rehman, Keith C. Hemmert, Atsuo Ochi, Mohsin Jamal, Justin R. Henning, Rocky Barilla, Juan P. Quesada, Constantinos P. Zambirinis, Kerry Tang, Melvin Ego-Osuala, Raghavendra S. Rao, Stephanie Greco, Michael Deutsch, Suchithra Narayan, H. Leon Pachter, Christopher S. Graffeo, Devrim Acehan, George Miller

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Dendritic cells (DC) are professional APCs that regulate innate and adaptive immunity. The role of fatty-acid synthesis in DC development and function is uncertain. We found that blockade of fatty-acid synthesis markedly decreases dendropoiesis in the liver and in primary and secondary lymphoid organs in mice. Human DC development from PBMC precursors was also diminished by blockade of fatty-acid synthesis. This was associated with higher rates of apoptosis in precursor cells and increased expression of cleaved caspase-3 and BCL-xL and downregulation of cyclin B1. Further, blockade of fatty-acid synthesis decreased DC expression of MHC class II, ICAM-1, B7-1, and B7-2 but increased their production of selected proinflammatory cytokines including IL-12 and MCP-1. Accordingly, inhibition of fatty-acid synthesis enhanced DC capacity to activate allogeneic as well as Ag-restricted CD4+ and CD8 + T cells and induce CTL responses. Further, blockade of fatty-acid synthesis increased DC expression of Notch ligands and enhanced their ability to activate NK cell immune phenotype and IFN-γ production. Because endoplasmic reticulum (ER) stress can augment the immunogenic function of APC, we postulated that this may account for the higher DC immunogenicity. We found that inhibition of fatty-acid synthesis resulted in elevated expression of numerous markers of ER stress in humans and mice and was associated with increased MAPK and Akt signaling. Further, lowering ER stress by 4-phenylbutyrate mitigated the enhanced immune stimulation associated with fatty-acid synthesis blockade. Our findings elucidate the role of fatty-acid synthesis in DC development and function and have implications to the design of DC vaccines for immunotherapy.

Original languageEnglish (US)
Pages (from-to)4640-4649
Number of pages10
JournalJournal of Immunology
Volume190
Issue number9
DOIs
StatePublished - May 1 2013

Fingerprint

Dendritic Cells
Fatty Acids
Endoplasmic Reticulum Stress
Cyclin B1
Adaptive Immunity
Intercellular Adhesion Molecule-1
Interleukin-12
Innate Immunity
Caspase 3
Natural Killer Cells
Immunotherapy
Down-Regulation
Vaccines
Apoptosis
Cytokines
Ligands
T-Lymphocytes
Phenotype
Liver

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Rehman, A., Hemmert, K. C., Ochi, A., Jamal, M., Henning, J. R., Barilla, R., ... Miller, G. (2013). Role of fatty-acid synthesis in dendritic cell generation and function. Journal of Immunology, 190(9), 4640-4649. https://doi.org/10.4049/jimmunol.1202312
Rehman, Adeel ; Hemmert, Keith C. ; Ochi, Atsuo ; Jamal, Mohsin ; Henning, Justin R. ; Barilla, Rocky ; Quesada, Juan P. ; Zambirinis, Constantinos P. ; Tang, Kerry ; Ego-Osuala, Melvin ; Rao, Raghavendra S. ; Greco, Stephanie ; Deutsch, Michael ; Narayan, Suchithra ; Leon Pachter, H. ; Graffeo, Christopher S. ; Acehan, Devrim ; Miller, George. / Role of fatty-acid synthesis in dendritic cell generation and function. In: Journal of Immunology. 2013 ; Vol. 190, No. 9. pp. 4640-4649.
@article{8ea51ede63824b7084a95a7879bbe74a,
title = "Role of fatty-acid synthesis in dendritic cell generation and function",
abstract = "Dendritic cells (DC) are professional APCs that regulate innate and adaptive immunity. The role of fatty-acid synthesis in DC development and function is uncertain. We found that blockade of fatty-acid synthesis markedly decreases dendropoiesis in the liver and in primary and secondary lymphoid organs in mice. Human DC development from PBMC precursors was also diminished by blockade of fatty-acid synthesis. This was associated with higher rates of apoptosis in precursor cells and increased expression of cleaved caspase-3 and BCL-xL and downregulation of cyclin B1. Further, blockade of fatty-acid synthesis decreased DC expression of MHC class II, ICAM-1, B7-1, and B7-2 but increased their production of selected proinflammatory cytokines including IL-12 and MCP-1. Accordingly, inhibition of fatty-acid synthesis enhanced DC capacity to activate allogeneic as well as Ag-restricted CD4+ and CD8 + T cells and induce CTL responses. Further, blockade of fatty-acid synthesis increased DC expression of Notch ligands and enhanced their ability to activate NK cell immune phenotype and IFN-γ production. Because endoplasmic reticulum (ER) stress can augment the immunogenic function of APC, we postulated that this may account for the higher DC immunogenicity. We found that inhibition of fatty-acid synthesis resulted in elevated expression of numerous markers of ER stress in humans and mice and was associated with increased MAPK and Akt signaling. Further, lowering ER stress by 4-phenylbutyrate mitigated the enhanced immune stimulation associated with fatty-acid synthesis blockade. Our findings elucidate the role of fatty-acid synthesis in DC development and function and have implications to the design of DC vaccines for immunotherapy.",
author = "Adeel Rehman and Hemmert, {Keith C.} and Atsuo Ochi and Mohsin Jamal and Henning, {Justin R.} and Rocky Barilla and Quesada, {Juan P.} and Zambirinis, {Constantinos P.} and Kerry Tang and Melvin Ego-Osuala and Rao, {Raghavendra S.} and Stephanie Greco and Michael Deutsch and Suchithra Narayan and {Leon Pachter}, H. and Graffeo, {Christopher S.} and Devrim Acehan and George Miller",
year = "2013",
month = "5",
day = "1",
doi = "10.4049/jimmunol.1202312",
language = "English (US)",
volume = "190",
pages = "4640--4649",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "9",

}

Rehman, A, Hemmert, KC, Ochi, A, Jamal, M, Henning, JR, Barilla, R, Quesada, JP, Zambirinis, CP, Tang, K, Ego-Osuala, M, Rao, RS, Greco, S, Deutsch, M, Narayan, S, Leon Pachter, H, Graffeo, CS, Acehan, D & Miller, G 2013, 'Role of fatty-acid synthesis in dendritic cell generation and function', Journal of Immunology, vol. 190, no. 9, pp. 4640-4649. https://doi.org/10.4049/jimmunol.1202312

Role of fatty-acid synthesis in dendritic cell generation and function. / Rehman, Adeel; Hemmert, Keith C.; Ochi, Atsuo; Jamal, Mohsin; Henning, Justin R.; Barilla, Rocky; Quesada, Juan P.; Zambirinis, Constantinos P.; Tang, Kerry; Ego-Osuala, Melvin; Rao, Raghavendra S.; Greco, Stephanie; Deutsch, Michael; Narayan, Suchithra; Leon Pachter, H.; Graffeo, Christopher S.; Acehan, Devrim; Miller, George.

In: Journal of Immunology, Vol. 190, No. 9, 01.05.2013, p. 4640-4649.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Role of fatty-acid synthesis in dendritic cell generation and function

AU - Rehman, Adeel

AU - Hemmert, Keith C.

AU - Ochi, Atsuo

AU - Jamal, Mohsin

AU - Henning, Justin R.

AU - Barilla, Rocky

AU - Quesada, Juan P.

AU - Zambirinis, Constantinos P.

AU - Tang, Kerry

AU - Ego-Osuala, Melvin

AU - Rao, Raghavendra S.

AU - Greco, Stephanie

AU - Deutsch, Michael

AU - Narayan, Suchithra

AU - Leon Pachter, H.

AU - Graffeo, Christopher S.

AU - Acehan, Devrim

AU - Miller, George

PY - 2013/5/1

Y1 - 2013/5/1

N2 - Dendritic cells (DC) are professional APCs that regulate innate and adaptive immunity. The role of fatty-acid synthesis in DC development and function is uncertain. We found that blockade of fatty-acid synthesis markedly decreases dendropoiesis in the liver and in primary and secondary lymphoid organs in mice. Human DC development from PBMC precursors was also diminished by blockade of fatty-acid synthesis. This was associated with higher rates of apoptosis in precursor cells and increased expression of cleaved caspase-3 and BCL-xL and downregulation of cyclin B1. Further, blockade of fatty-acid synthesis decreased DC expression of MHC class II, ICAM-1, B7-1, and B7-2 but increased their production of selected proinflammatory cytokines including IL-12 and MCP-1. Accordingly, inhibition of fatty-acid synthesis enhanced DC capacity to activate allogeneic as well as Ag-restricted CD4+ and CD8 + T cells and induce CTL responses. Further, blockade of fatty-acid synthesis increased DC expression of Notch ligands and enhanced their ability to activate NK cell immune phenotype and IFN-γ production. Because endoplasmic reticulum (ER) stress can augment the immunogenic function of APC, we postulated that this may account for the higher DC immunogenicity. We found that inhibition of fatty-acid synthesis resulted in elevated expression of numerous markers of ER stress in humans and mice and was associated with increased MAPK and Akt signaling. Further, lowering ER stress by 4-phenylbutyrate mitigated the enhanced immune stimulation associated with fatty-acid synthesis blockade. Our findings elucidate the role of fatty-acid synthesis in DC development and function and have implications to the design of DC vaccines for immunotherapy.

AB - Dendritic cells (DC) are professional APCs that regulate innate and adaptive immunity. The role of fatty-acid synthesis in DC development and function is uncertain. We found that blockade of fatty-acid synthesis markedly decreases dendropoiesis in the liver and in primary and secondary lymphoid organs in mice. Human DC development from PBMC precursors was also diminished by blockade of fatty-acid synthesis. This was associated with higher rates of apoptosis in precursor cells and increased expression of cleaved caspase-3 and BCL-xL and downregulation of cyclin B1. Further, blockade of fatty-acid synthesis decreased DC expression of MHC class II, ICAM-1, B7-1, and B7-2 but increased their production of selected proinflammatory cytokines including IL-12 and MCP-1. Accordingly, inhibition of fatty-acid synthesis enhanced DC capacity to activate allogeneic as well as Ag-restricted CD4+ and CD8 + T cells and induce CTL responses. Further, blockade of fatty-acid synthesis increased DC expression of Notch ligands and enhanced their ability to activate NK cell immune phenotype and IFN-γ production. Because endoplasmic reticulum (ER) stress can augment the immunogenic function of APC, we postulated that this may account for the higher DC immunogenicity. We found that inhibition of fatty-acid synthesis resulted in elevated expression of numerous markers of ER stress in humans and mice and was associated with increased MAPK and Akt signaling. Further, lowering ER stress by 4-phenylbutyrate mitigated the enhanced immune stimulation associated with fatty-acid synthesis blockade. Our findings elucidate the role of fatty-acid synthesis in DC development and function and have implications to the design of DC vaccines for immunotherapy.

UR - http://www.scopus.com/inward/record.url?scp=84876813301&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84876813301&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.1202312

DO - 10.4049/jimmunol.1202312

M3 - Article

C2 - 23536633

AN - SCOPUS:84876813301

VL - 190

SP - 4640

EP - 4649

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 9

ER -

Rehman A, Hemmert KC, Ochi A, Jamal M, Henning JR, Barilla R et al. Role of fatty-acid synthesis in dendritic cell generation and function. Journal of Immunology. 2013 May 1;190(9):4640-4649. https://doi.org/10.4049/jimmunol.1202312