Toll-like receptors (TLRs) function as primary sensors that elicit coordinated innate immune defenses through recognition of microbial products and induction of immune and proinflammatory genes. Here we report the identification and biological characterization of a lipopolysaccharide (LPS)-like molecule extracted from the cyanobacterium Oscillatoria Planktothrix FP1 (cyanobacterial product [CyP]) that is not stimulatory per se but acts as a potent and selective antagonist of bacterial LPS. CyP binds to MD-2 and efficiently competes with LPS for binding to the TLR4–MD-2 receptor complex. The addition of CyP together with LPS completely inhibited both MyD88- and TRIF-dependent pathways and suppressed the whole LPS-induced gene transcription program in human dendritic cells (DCs). CyP protected mice from endotoxin shock in spite of a lower capacity to inhibit LPS stimulation of mouse DCs. Interestingly, the delayed addition of CyP to DCs responding to LPS strongly inhibited signaling and cytokine production by immediate down-regulation of inflammatory cytokine mRNAs while not affecting other aspects of DC maturation, such as expression of major histocompatibility complex molecules, costimulatory molecules, and CCR7. Collectively, these results indicate that CyP is a potent competitive inhibitor of LPS in vitro and in vivo and reveal the requirement of sustained TLR4 stimulation for induction of cytokine genes in human DCs.
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12 June 2006
Article|
May 22 2006
A cyanobacterial LPS antagonist prevents endotoxin shock and blocks sustained TLR4 stimulation required for cytokine expression
Annalisa Macagno,
Annalisa Macagno
1Institute for Research in Biomedicine, CH-6500 Bellinzona, Switzerland
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Monica Molteni,
Monica Molteni
2University of Insubria, I-21100 Varese, Italy
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Andrea Rinaldi,
Andrea Rinaldi
3Oncology Institute of Southern Switzerland, CH-6500 Bellinzona, Switzerland
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Francesco Bertoni,
Francesco Bertoni
3Oncology Institute of Southern Switzerland, CH-6500 Bellinzona, Switzerland
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Antonio Lanzavecchia,
Antonio Lanzavecchia
1Institute for Research in Biomedicine, CH-6500 Bellinzona, Switzerland
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Carlo Rossetti,
Carlo Rossetti
2University of Insubria, I-21100 Varese, Italy
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Federica Sallusto
Federica Sallusto
1Institute for Research in Biomedicine, CH-6500 Bellinzona, Switzerland
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Annalisa Macagno
1Institute for Research in Biomedicine, CH-6500 Bellinzona, Switzerland
Monica Molteni
2University of Insubria, I-21100 Varese, Italy
Andrea Rinaldi
3Oncology Institute of Southern Switzerland, CH-6500 Bellinzona, Switzerland
Francesco Bertoni
3Oncology Institute of Southern Switzerland, CH-6500 Bellinzona, Switzerland
Antonio Lanzavecchia
1Institute for Research in Biomedicine, CH-6500 Bellinzona, Switzerland
Carlo Rossetti
2University of Insubria, I-21100 Varese, Italy
Federica Sallusto
1Institute for Research in Biomedicine, CH-6500 Bellinzona, Switzerland
CORRESPONDENCE Annalisa Macagno: [email protected] OR Federica Sallusto: [email protected]
Abbreviations used: CyP, cyanobacterial product; PGN, peptidoglican; TLR, Toll-like receptor.
Received:
January 17 2006
Accepted:
April 23 2006
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2006
J Exp Med (2006) 203 (6): 1481–1492.
Article history
Received:
January 17 2006
Accepted:
April 23 2006
Citation
Annalisa Macagno, Monica Molteni, Andrea Rinaldi, Francesco Bertoni, Antonio Lanzavecchia, Carlo Rossetti, Federica Sallusto; A cyanobacterial LPS antagonist prevents endotoxin shock and blocks sustained TLR4 stimulation required for cytokine expression . J Exp Med 12 June 2006; 203 (6): 1481–1492. doi: https://doi.org/10.1084/jem.20060136
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