Selective activation of the p38 MAPK pathway by synthetic monophosphoryl lipid A

Caglar Cekic, Carolyn R. Casella, Chelsea A. Eaves, Atsushi Matsuzawa, Hidenori Ichijo, Thomas C. Mitchell

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

TLR4 stimulation by lipopolysaccharide can cause both MAL/MyD88- and TRAM/TRIF (Toll IL-1 receptor domain-containing adaptor-inducing IFNβ)-dependent signaling events. Monophosphoryl lipid A (MPLA), a low toxicity derivative of endotoxic lipopolysaccharide, enhances antibody responses, T cell expansion, and recall responses against antigens without causing excessive inflammatory side effects. Previously, we proposed that TRIF-biased activation of TLR4 by MPLA is responsible for its reduced toxicity while retaining potent adjuvant effects. However, some TRIF-associated genes, such as MCP-1, are only weakly expressed, and some MyD88-associated inflammatory and anti-inflammatory cytokines, such as tumor necrosis factor α and interleukin-10, are strongly activated after MPLA stimulation despite weak NF-κB but strong IRF3 activation. We now report that synthetic derivatives of MPLA retained TRIF bias as compared with synthetic diphosphoryl lipid A, indicating a change in a single phosphoryl group is sufficient for TRIF-biased TLR4 stimulation. We extend our previous observations by showing that sMLA induces strong p38 MAPK but weak JNK activation, resulting in high IP-10 (interferon-inducible protein 10), tumor necrosis factorb, and interleukin-10 but low MCP-1 transcript levels. Results of this study identify a novel biochemical mechanism for regulation of sMLA-induced gene expression.

Original languageEnglish
Pages (from-to)31982-31991
Number of pages10
JournalJournal of Biological Chemistry
Volume284
Issue number46
DOIs
Publication statusPublished - 2009 Nov 30
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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