PMID- 12421970
OWN - NLM
STAT- MEDLINE
DCOM- 20030114
LR  - 20190515
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 169
IP  - 10
DP  - 2002 Nov 15
TI  - Toll-like receptor 4 and Toll-IL-1 receptor domain-containing adapter protein 
      (TIRAP)/myeloid differentiation protein 88 adapter-like (Mal) contribute to 
      maximal IL-6 expression in macrophages.
PG  - 5874-80
AB  - Previous studies have shown that engagement of Toll-like receptors (TLR) 2 and 4 
      can induce macrophages to express a variety of proinflammatory cytokines. We have 
      recently demonstrated that TLR2 agonists poorly induce a subset of TLR4-inducible 
      proinflammatory genes (e.g., inducible protein (IP)-10, inducible NO synthase 
      (iNOS), monocyte chemoattractant protein-5, IL-12p40), due in part to 
      differential activation of IFN-beta production and phosphorylation of the 
      transcription factor STAT1. TLR4, but not TLR2, agonists can induce IFN-beta 
      expression via a mechanism that requires the adapter protein Toll-IL-1R 
      domain-containing adapter protein (TIRAP)/myeloid differentiation protein 88 
      (MyD88) adapter-like (Mal), but not the adapter protein MyD88. Thus, the failure 
      of TLR2 agonists to induce STAT1-dependent genes results, in part, from their 
      failure to induce the expression of IFN-beta. In this study, we show that IL-6 
      expression is also preferentially induced by activation of TLR4. TLR4-dependent 
      induction of IL-6 expression did require Toll-IL-1R domain-containing adapter 
      protein (TIRAP)/MyD88 adapter-like (Mal), but unlike iNOS and IP-10, it did not 
      require the expression of IFN-beta. Although exogenous IFN-beta and IFN-gamma 
      could synergize with TLR2 agonists to restore high levels of iNOS expression and 
      NO production, these IFNs could not synergize with TLR2 agonists to induce high 
      levels of IL-6. Similarly, neutralizing anti-IFN Abs could block iNOS gene 
      expression in LPS-stimulated murine macrophages, whereas these Abs had little 
      effect on IL-6 gene expression in these cells. Together, these studies 
      demonstrate that IL-6, like iNOS and IP-10, is differentially expressed in 
      macrophages stimulated via TLR2 vs TLR4, although these differences appear to 
      arise from distinct signaling mechanisms.
FAU - Schilling, Dagmar
AU  - Schilling D
AD  - Pulmonary Center, School of Medicine, Boston University, Boston, MA 02118, USA.
FAU - Thomas, Karen
AU  - Thomas K
FAU - Nixdorff, Kathryn
AU  - Nixdorff K
FAU - Vogel, Stefanie N
AU  - Vogel SN
FAU - Fenton, Matthew J
AU  - Fenton MJ
LA  - eng
GR  - AI 18797/AI/NIAID NIH HHS/United States
GR  - AI 47233/AI/NIAID 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 (58 kDa tumor necrosis factor-inducing protein, Mycobacterium tuberculosis)
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Antigens, Differentiation)
RN  - 0 (Bacterial Proteins)
RN  - 0 (Carrier Proteins)
RN  - 0 (Drosophila Proteins)
RN  - 0 (Interferon Type I)
RN  - 0 (Interleukin-6)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Lipoproteins)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Myd88 protein, mouse)
RN  - 0 (Myeloid Differentiation Factor 88)
RN  - 0 (Proteins)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (Receptors, Immunologic)
RN  - 0 (Receptors, Interleukin-1)
RN  - 0 (TIRAP protein, mouse)
RN  - 0 (Toll-Like Receptor 2)
RN  - 0 (Toll-Like Receptor 4)
RN  - 0 (Toll-Like Receptors)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 77238-31-4 (Interferon-beta)
RN  - 82115-62-6 (Interferon-gamma)
RN  - 87420-41-5 (2,3-bis(palmitoyloxy)-2-propyl-1-palmitoylcysteine)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
RN  - EC 1.14.13.39 (Nos2 protein, mouse)
RN  - EC 2.7.11.1 (eIF-2 Kinase)
RN  - K848JZ4886 (Cysteine)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing
MH  - Amino Acid Sequence
MH  - Animals
MH  - Antigens, Differentiation/*physiology
MH  - Bacterial Proteins/pharmacology
MH  - Bone Marrow Cells/immunology/metabolism
MH  - Carrier Proteins/*physiology
MH  - Cell Line
MH  - Cysteine/*analogs & derivatives/pharmacology
MH  - *Drosophila Proteins
MH  - Drug Synergism
MH  - Interferon Type I/metabolism/physiology
MH  - Interferon-beta/pharmacology
MH  - Interferon-gamma/pharmacology
MH  - Interleukin-6/*biosynthesis/genetics
MH  - Lipopolysaccharides/pharmacology
MH  - Lipoproteins/pharmacology
MH  - Macrophages/*immunology/*metabolism
MH  - Macrophages, Peritoneal/immunology/metabolism
MH  - Membrane Glycoproteins/agonists/*physiology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Molecular Sequence Data
MH  - Myeloid Differentiation Factor 88
MH  - Nitric Oxide Synthase/biosynthesis/genetics
MH  - Nitric Oxide Synthase Type II
MH  - Protein Biosynthesis
MH  - Proteins/physiology
MH  - Receptors, Cell Surface/agonists/*physiology
MH  - Receptors, Immunologic/*physiology
MH  - Receptors, Interleukin-1/*physiology
MH  - Signal Transduction/drug effects/*immunology
MH  - Toll-Like Receptor 2
MH  - Toll-Like Receptor 4
MH  - Toll-Like Receptors
MH  - Tumor Necrosis Factor-alpha/pharmacology
MH  - eIF-2 Kinase/deficiency/genetics/physiology
EDAT- 2002/11/08 04:00
MHDA- 2003/01/15 04:00
CRDT- 2002/11/08 04:00
PHST- 2002/11/08 04:00 [pubmed]
PHST- 2003/01/15 04:00 [medline]
PHST- 2002/11/08 04:00 [entrez]
AID - 10.4049/jimmunol.169.10.5874 [doi]
PST - ppublish
SO  - J Immunol. 2002 Nov 15;169(10):5874-80. doi: 10.4049/jimmunol.169.10.5874.