PMID- 10570307
OWN - NLM
STAT- MEDLINE
DCOM- 19991220
LR  - 20181130
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 163
IP  - 11
DP  - 1999 Dec 1
TI  - Transcriptional and translational regulation of inflammatory mediator production 
      by endogenous TGF-beta in macrophages that have ingested apoptotic cells.
PG  - 6164-72
AB  - We recently reported that phagocytosis of apoptotic cells inhibits the release of 
      inflammatory cytokines by human macrophages. In this paper we show that apoptotic 
      cell uptake by mouse J774 macrophages also inhibits the synthesis and secretion 
      of the chemokines, macrophage inflammatory protein-2 (Mip-2), KC, and Mip-1alpha 
      (but not that of monocyte chemoattractant protein-1 (MCP-1)/JE), and increases 
      TGF-beta formation. Anti-TGF-beta neutralizing Abs largely reversed the 
      inhibitory effect of apoptotic cell uptake, and accordingly, exogenous TGF-beta 
      down-regulated the synthesis of the same mediators. Apoptotic cell ingestion or 
      TGF-beta also inhibited Mip-2 and Mip-1alpha gene expression in LPS-treated J774 
      cells, whereas TNF-alpha mRNA levels were unaffected. Importantly, TGF-beta 
      pretreatment of J774 cells did not significantly alter chemokine and TNF mRNA 
      stability. Finally, we found that apoptotic cell uptake and TGF-beta did not 
      modulate NF-kappaB or AP-1 DNA binding in J774 cells. We conclude that the 
      decreased production of chemokines and TNF resulting from apoptotic cell 
      ingestion is largely mediated by a common event, i.e., feedback inhibition by 
      endogenous TGF-beta, but involves different mechanisms. Whereas TNF-alpha 
      production appears to be translationally down-regulated, the suppression of most 
      chemokines investigated appears to reflect transcriptional inhibition. In a 
      broader context, the impairment of chemokine and TNF generation by apoptotic cell 
      uptake might represent an important mechanism contributing to the resolution of 
      inflammation. An additional consequence could be the selective recruitment of 
      monocytes into inflammatory sites, as MCP-1/JE production by mouse macrophages 
      was unaffected by apoptotic cell uptake, in contrast to other chemokines.
FAU - McDonald, P P
AU  - McDonald PP
AD  - National Jewish Medical and Research Center, Denver, CO 80206, USA. 
      patrick.mcdonald@courier.usherbca
FAU - Fadok, V A
AU  - Fadok VA
FAU - Bratton, D
AU  - Bratton D
FAU - Henson, P M
AU  - Henson PM
LA  - eng
GR  - GM48211/GM/NIGMS NIH HHS/United States
GR  - HL34303/HL/NHLBI NIH HHS/United States
GR  - HL60980/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Chemokine CCL2)
RN  - 0 (Chemokines)
RN  - 0 (Inflammation Mediators)
RN  - 0 (NF-kappa B)
RN  - 0 (Transcription Factor AP-1)
RN  - 0 (Transforming Growth Factor beta)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Animals
MH  - Apoptosis/*immunology
MH  - Chemokine CCL2/biosynthesis
MH  - Chemokines/metabolism
MH  - Chemotaxis, Leukocyte
MH  - Gene Expression Regulation
MH  - Humans
MH  - Inflammation Mediators/*metabolism
MH  - Jurkat Cells
MH  - Macrophages/*immunology
MH  - Mice
MH  - Molecular Mimicry
MH  - Monocytes/immunology
MH  - NF-kappa B/metabolism
MH  - Phagocytosis/*immunology
MH  - Protein Biosynthesis
MH  - Transcription Factor AP-1/metabolism
MH  - Transcription, Genetic
MH  - Transforming Growth Factor beta/metabolism
MH  - Tumor Necrosis Factor-alpha/metabolism
EDAT- 1999/11/26 00:00
MHDA- 1999/11/26 00:01
CRDT- 1999/11/26 00:00
PHST- 1999/11/26 00:00 [pubmed]
PHST- 1999/11/26 00:01 [medline]
PHST- 1999/11/26 00:00 [entrez]
AID - ji_v163n11p6164 [pii]
PST - ppublish
SO  - J Immunol. 1999 Dec 1;163(11):6164-72.