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Superantigen recognition by HLA class II on monocytes up-regulates toll-like receptor 4 and enhances proinflammatory responses to endotoxin

Superantigen recognition by HLA class II on monocytes up-regulates toll-like receptor 4 and enhances proinflammatory responses to endotoxin
Superantigen recognition by HLA class II on monocytes up-regulates toll-like receptor 4 and enhances proinflammatory responses to endotoxin

The devastating systemic effects of bacterial superantigens may be explained by powerful proinflammatory synergy with lipopolysaccharide (LPS). However, the mechanism underlying this phenomenon remains unclear and has never been investigated in humans. Specifically, there is no known link between superantigen-induced immune effects and the pattern recognition of LPS at toll-like receptor 4 (TLR4). Here we show that bacterial superantigens induce rapid transcription and increased membrane expression of TLR4 in primary human monocytes by ligation of major histocompatibility complex (MHC) class II. We also demonstrate that superantigens are solely responsible for monocyte TLR4 up-regulation induced by products from Gram-positive bacteria. In parallel with enhanced TLR4 expression, priming of purified monocytes or mixed peripheral blood mononuclear cells with superantigens significantly enhanced the induction of proinflammatory cytokines by known TLR4 ligands. Staphylococcal enterotoxin A constructs containing targeted mutations were used to demonstrate a requirement for MHC class II ligation in both TLR4 up-regulation and enhanced responses to endotoxin. In contrast to results from animal models, superantigen-endotoxin interaction was not dependent on T-cell receptor ligation by superantigen or interferon gamma production. Pattern recognition of bacterial superantigens by MHC class II receptors may exacerbate the proinflammatory response of monocytes to Gram-negative infection or endotoxin by up-regulation of TLR4.

Cytokines, Gram-Negative Bacteria, Gram-Positive Bacteria, Histocompatibility Antigens Class II, Humans, Inflammation, Ligands, Lipopolysaccharides, Membrane Glycoproteins, Monocytes, Receptors, Cell Surface, Superantigens, Toll-Like Receptor 4, Toll-Like Receptors, Transcription, Genetic, Up-Regulation, Journal Article, Research Support, Non-U.S. Gov't
0006-4971
3655-3662
Hopkins, Philip A
9735c9b1-ace8-4988-bc1d-8fdc7cd80930
Fraser, John D
e6bc02a5-3e7f-4287-b4bb-62c7be2ce379
Pridmore, Alison C
b704c202-afcc-4fde-9169-48e51f9fa0b0
Russell, Hugh H
cf5c39bb-7da0-414c-aea8-f4c2d8f9f91d
Read, Robert C
b5caca7b-0063-438a-b703-7ecbb6fc2b51
Sriskandan, Shiranee
f71ce728-08fb-4261-b3e6-7be16d72627e
Hopkins, Philip A
9735c9b1-ace8-4988-bc1d-8fdc7cd80930
Fraser, John D
e6bc02a5-3e7f-4287-b4bb-62c7be2ce379
Pridmore, Alison C
b704c202-afcc-4fde-9169-48e51f9fa0b0
Russell, Hugh H
cf5c39bb-7da0-414c-aea8-f4c2d8f9f91d
Read, Robert C
b5caca7b-0063-438a-b703-7ecbb6fc2b51
Sriskandan, Shiranee
f71ce728-08fb-4261-b3e6-7be16d72627e

Hopkins, Philip A, Fraser, John D, Pridmore, Alison C, Russell, Hugh H, Read, Robert C and Sriskandan, Shiranee (2005) Superantigen recognition by HLA class II on monocytes up-regulates toll-like receptor 4 and enhances proinflammatory responses to endotoxin. Blood, 105 (9), 3655-3662. (doi:10.1182/blood-2004-07-2523).

Record type: Article

Abstract

The devastating systemic effects of bacterial superantigens may be explained by powerful proinflammatory synergy with lipopolysaccharide (LPS). However, the mechanism underlying this phenomenon remains unclear and has never been investigated in humans. Specifically, there is no known link between superantigen-induced immune effects and the pattern recognition of LPS at toll-like receptor 4 (TLR4). Here we show that bacterial superantigens induce rapid transcription and increased membrane expression of TLR4 in primary human monocytes by ligation of major histocompatibility complex (MHC) class II. We also demonstrate that superantigens are solely responsible for monocyte TLR4 up-regulation induced by products from Gram-positive bacteria. In parallel with enhanced TLR4 expression, priming of purified monocytes or mixed peripheral blood mononuclear cells with superantigens significantly enhanced the induction of proinflammatory cytokines by known TLR4 ligands. Staphylococcal enterotoxin A constructs containing targeted mutations were used to demonstrate a requirement for MHC class II ligation in both TLR4 up-regulation and enhanced responses to endotoxin. In contrast to results from animal models, superantigen-endotoxin interaction was not dependent on T-cell receptor ligation by superantigen or interferon gamma production. Pattern recognition of bacterial superantigens by MHC class II receptors may exacerbate the proinflammatory response of monocytes to Gram-negative infection or endotoxin by up-regulation of TLR4.

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More information

Published date: 1 May 2005
Keywords: Cytokines, Gram-Negative Bacteria, Gram-Positive Bacteria, Histocompatibility Antigens Class II, Humans, Inflammation, Ligands, Lipopolysaccharides, Membrane Glycoproteins, Monocytes, Receptors, Cell Surface, Superantigens, Toll-Like Receptor 4, Toll-Like Receptors, Transcription, Genetic, Up-Regulation, Journal Article, Research Support, Non-U.S. Gov't

Identifiers

Local EPrints ID: 416427
URI: http://eprints.soton.ac.uk/id/eprint/416427
ISSN: 0006-4971
PURE UUID: 4f49d6c7-b27c-4522-bed5-b54713b92e5e
ORCID for Robert C Read: ORCID iD orcid.org/0000-0002-4297-6728

Catalogue record

Date deposited: 15 Dec 2017 17:30
Last modified: 10 Nov 2021 03:30

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Contributors

Author: Philip A Hopkins
Author: John D Fraser
Author: Alison C Pridmore
Author: Hugh H Russell
Author: Robert C Read ORCID iD
Author: Shiranee Sriskandan

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