FANCA and FANCC modulate TLR and p38 MAPK-dependent expression of IL-1β in macrophages.

Michael R. Garbati, Laura E. Hays, Winifred Keeble, Jane E. Yates, R. Keaney Rathbun, Grover C. Bagby

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Hematopoietic stem and progenitor cells with inactivated Fanconi anemia (FA) genes, FANCA and FANCC, are hypersensitive to inflammatory cytokines. One of these, tumor necrosis factor α (TNF-α), is also overproduced by FA mononuclear phagocytes in response to certain Toll-like receptor (TLR) agonists, creating an autoinhibitory loop that may contribute to the pathogenesis of progressive bone marrow (BM) failure and selection of TNF-α-resistant leukemic stem cell clones. In macrophages, the TNF-α overproduction phenotype depends on p38 mitogen-activated protein kinase (MAPK), an enzyme also known to induce expression of other inflammatory cytokines, including interleukin 1β (IL-1β). Reasoning that IL-1β might be involved in a like autoinhibitory loop, we determined that (1) TLR activation of FANCA- and FANCC-deficient macrophages induced overproduction of both TNF-α and IL-1β in a p38-dependent manner; (2) exposure of Fancc-deficient BM progenitors to IL-1β potently suppressed the expansion of multipotent progenitor cells in vitro; and (3) although TNF-α overexpression in FA cells is controlled posttranscriptionally by the p38 substrate MAPKAPK-2, p38-dependent overproduction of IL-1β is controlled transcriptionally. We suggest that multiple inflammatory cytokines overproduced by FANCA- and FANCC-deficient mononuclear phagocytes may contribute to the progressive BM failure that characterizes FA, and that to achieve suppression of this proinflammatory state, p38 is a more promising molecular therapeutic target than either IL-1β or TNF-α alone.

Original languageEnglish (US)
Pages (from-to)3197-3205
Number of pages9
JournalBlood
Volume122
Issue number18
StatePublished - Oct 31 2013
Externally publishedYes

Fingerprint

Macrophages
Toll-Like Receptors
p38 Mitogen-Activated Protein Kinases
Interleukin-1
Fanconi Anemia
Tumor Necrosis Factor-alpha
Bone
Bone Marrow
Phagocytes
Cytokines
Hematopoietic Stem Cells
Stem Cells
Toll-Like Receptor 1
Stem cells
Clone Cells
Genes
Chemical activation
Phenotype
Substrates
Enzymes

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology
  • Medicine(all)

Cite this

Garbati, M. R., Hays, L. E., Keeble, W., Yates, J. E., Rathbun, R. K., & Bagby, G. C. (2013). FANCA and FANCC modulate TLR and p38 MAPK-dependent expression of IL-1β in macrophages. Blood, 122(18), 3197-3205.

FANCA and FANCC modulate TLR and p38 MAPK-dependent expression of IL-1β in macrophages. / Garbati, Michael R.; Hays, Laura E.; Keeble, Winifred; Yates, Jane E.; Rathbun, R. Keaney; Bagby, Grover C.

In: Blood, Vol. 122, No. 18, 31.10.2013, p. 3197-3205.

Research output: Contribution to journalArticle

Garbati, MR, Hays, LE, Keeble, W, Yates, JE, Rathbun, RK & Bagby, GC 2013, 'FANCA and FANCC modulate TLR and p38 MAPK-dependent expression of IL-1β in macrophages.', Blood, vol. 122, no. 18, pp. 3197-3205.
Garbati MR, Hays LE, Keeble W, Yates JE, Rathbun RK, Bagby GC. FANCA and FANCC modulate TLR and p38 MAPK-dependent expression of IL-1β in macrophages. Blood. 2013 Oct 31;122(18):3197-3205.
Garbati, Michael R. ; Hays, Laura E. ; Keeble, Winifred ; Yates, Jane E. ; Rathbun, R. Keaney ; Bagby, Grover C. / FANCA and FANCC modulate TLR and p38 MAPK-dependent expression of IL-1β in macrophages. In: Blood. 2013 ; Vol. 122, No. 18. pp. 3197-3205.
@article{c9d26d35dc44488d9e75a6bdcec07794,
title = "FANCA and FANCC modulate TLR and p38 MAPK-dependent expression of IL-1β in macrophages.",
abstract = "Hematopoietic stem and progenitor cells with inactivated Fanconi anemia (FA) genes, FANCA and FANCC, are hypersensitive to inflammatory cytokines. One of these, tumor necrosis factor α (TNF-α), is also overproduced by FA mononuclear phagocytes in response to certain Toll-like receptor (TLR) agonists, creating an autoinhibitory loop that may contribute to the pathogenesis of progressive bone marrow (BM) failure and selection of TNF-α-resistant leukemic stem cell clones. In macrophages, the TNF-α overproduction phenotype depends on p38 mitogen-activated protein kinase (MAPK), an enzyme also known to induce expression of other inflammatory cytokines, including interleukin 1β (IL-1β). Reasoning that IL-1β might be involved in a like autoinhibitory loop, we determined that (1) TLR activation of FANCA- and FANCC-deficient macrophages induced overproduction of both TNF-α and IL-1β in a p38-dependent manner; (2) exposure of Fancc-deficient BM progenitors to IL-1β potently suppressed the expansion of multipotent progenitor cells in vitro; and (3) although TNF-α overexpression in FA cells is controlled posttranscriptionally by the p38 substrate MAPKAPK-2, p38-dependent overproduction of IL-1β is controlled transcriptionally. We suggest that multiple inflammatory cytokines overproduced by FANCA- and FANCC-deficient mononuclear phagocytes may contribute to the progressive BM failure that characterizes FA, and that to achieve suppression of this proinflammatory state, p38 is a more promising molecular therapeutic target than either IL-1β or TNF-α alone.",
author = "Garbati, {Michael R.} and Hays, {Laura E.} and Winifred Keeble and Yates, {Jane E.} and Rathbun, {R. Keaney} and Bagby, {Grover C.}",
year = "2013",
month = "10",
day = "31",
language = "English (US)",
volume = "122",
pages = "3197--3205",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "18",

}

TY - JOUR

T1 - FANCA and FANCC modulate TLR and p38 MAPK-dependent expression of IL-1β in macrophages.

AU - Garbati, Michael R.

AU - Hays, Laura E.

AU - Keeble, Winifred

AU - Yates, Jane E.

AU - Rathbun, R. Keaney

AU - Bagby, Grover C.

PY - 2013/10/31

Y1 - 2013/10/31

N2 - Hematopoietic stem and progenitor cells with inactivated Fanconi anemia (FA) genes, FANCA and FANCC, are hypersensitive to inflammatory cytokines. One of these, tumor necrosis factor α (TNF-α), is also overproduced by FA mononuclear phagocytes in response to certain Toll-like receptor (TLR) agonists, creating an autoinhibitory loop that may contribute to the pathogenesis of progressive bone marrow (BM) failure and selection of TNF-α-resistant leukemic stem cell clones. In macrophages, the TNF-α overproduction phenotype depends on p38 mitogen-activated protein kinase (MAPK), an enzyme also known to induce expression of other inflammatory cytokines, including interleukin 1β (IL-1β). Reasoning that IL-1β might be involved in a like autoinhibitory loop, we determined that (1) TLR activation of FANCA- and FANCC-deficient macrophages induced overproduction of both TNF-α and IL-1β in a p38-dependent manner; (2) exposure of Fancc-deficient BM progenitors to IL-1β potently suppressed the expansion of multipotent progenitor cells in vitro; and (3) although TNF-α overexpression in FA cells is controlled posttranscriptionally by the p38 substrate MAPKAPK-2, p38-dependent overproduction of IL-1β is controlled transcriptionally. We suggest that multiple inflammatory cytokines overproduced by FANCA- and FANCC-deficient mononuclear phagocytes may contribute to the progressive BM failure that characterizes FA, and that to achieve suppression of this proinflammatory state, p38 is a more promising molecular therapeutic target than either IL-1β or TNF-α alone.

AB - Hematopoietic stem and progenitor cells with inactivated Fanconi anemia (FA) genes, FANCA and FANCC, are hypersensitive to inflammatory cytokines. One of these, tumor necrosis factor α (TNF-α), is also overproduced by FA mononuclear phagocytes in response to certain Toll-like receptor (TLR) agonists, creating an autoinhibitory loop that may contribute to the pathogenesis of progressive bone marrow (BM) failure and selection of TNF-α-resistant leukemic stem cell clones. In macrophages, the TNF-α overproduction phenotype depends on p38 mitogen-activated protein kinase (MAPK), an enzyme also known to induce expression of other inflammatory cytokines, including interleukin 1β (IL-1β). Reasoning that IL-1β might be involved in a like autoinhibitory loop, we determined that (1) TLR activation of FANCA- and FANCC-deficient macrophages induced overproduction of both TNF-α and IL-1β in a p38-dependent manner; (2) exposure of Fancc-deficient BM progenitors to IL-1β potently suppressed the expansion of multipotent progenitor cells in vitro; and (3) although TNF-α overexpression in FA cells is controlled posttranscriptionally by the p38 substrate MAPKAPK-2, p38-dependent overproduction of IL-1β is controlled transcriptionally. We suggest that multiple inflammatory cytokines overproduced by FANCA- and FANCC-deficient mononuclear phagocytes may contribute to the progressive BM failure that characterizes FA, and that to achieve suppression of this proinflammatory state, p38 is a more promising molecular therapeutic target than either IL-1β or TNF-α alone.

UR - http://www.scopus.com/inward/record.url?scp=84891609587&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84891609587&partnerID=8YFLogxK

M3 - Article

VL - 122

SP - 3197

EP - 3205

JO - Blood

JF - Blood

SN - 0006-4971

IS - 18

ER -