Abstract
Despite anti-TNF therapy advancements for inflammatory diseases such as rheumatoid arthritis, the burden of diseases remains high. An 11-mer TNF peptide, TNF70-80, is known to stimulate selective functional responses compared to the parent TNF molecule. Here, we show that TNF70-80 binds to the TNF receptor, activating p38 MAP kinase through TNF receptor-associated factor 2. Using truncated TNFR mutants, we identify the sequence in TNFRI which enables p38 activation by TNF70-80. Peptides with this TNFRI sequence, such as TNFRI206-211 bind to TNF and inhibit TNF-induced p38 activation, respiratory burst, cytokine production and adhesion receptor expression but not F-Met-Leu-Phe-induced respiratory burst in neutrophils. TNFRI206-211 does not prevent TNF binding to TNFRI or TNF-induced stimulation of ERK, JNK and NF-κB. TNFRI206-211 inhibits bacterial lipopolysaccharide-induced peritonitis, carrageenan-induced and antigen-induced paw inflammation, and respiratory syncytial virus-induced lung inflammation in mice. Our findings suggest a way of targeting TNF-p38 pathway to treat chronic inflammatory disorders.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents / chemistry
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Anti-Inflammatory Agents / metabolism
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Anti-Inflammatory Agents / pharmacology*
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Arthritis, Experimental / drug therapy*
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Arthritis, Experimental / genetics
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Arthritis, Experimental / immunology
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Arthritis, Experimental / pathology
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Disease Models, Animal
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Female
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Gene Expression Regulation
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Humans
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Lipopolysaccharides / antagonists & inhibitors
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Lipopolysaccharides / pharmacology
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Mice
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Mice, Inbred BALB C
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Neutrophils / cytology
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Neutrophils / drug effects
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Neutrophils / immunology
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Peptide Fragments / biosynthesis
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Peptide Fragments / genetics
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Peptide Fragments / pharmacology*
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Peritonitis / drug therapy*
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Peritonitis / genetics
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Peritonitis / immunology
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Peritonitis / pathology
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Platelet Glycoprotein GPIb-IX Complex / genetics
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Platelet Glycoprotein GPIb-IX Complex / immunology
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Pneumonia / drug therapy*
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Pneumonia / genetics
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Pneumonia / immunology
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Pneumonia / pathology
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Pneumonia, Viral / drug therapy*
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Pneumonia, Viral / genetics
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Pneumonia, Viral / immunology
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Pneumonia, Viral / pathology
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Protein Binding
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Receptors, Tumor Necrosis Factor / antagonists & inhibitors
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Receptors, Tumor Necrosis Factor / genetics
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Receptors, Tumor Necrosis Factor / immunology
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Respiratory Burst / drug effects
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Respiratory Syncytial Viruses / immunology
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Respiratory Syncytial Viruses / pathogenicity
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Signal Transduction
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / immunology
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / immunology
Substances
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Anti-Inflammatory Agents
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Lipopolysaccharides
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Peptide Fragments
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Platelet Glycoprotein GPIb-IX Complex
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Receptors, Tumor Necrosis Factor
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Tumor Necrosis Factor-alpha
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adhesion receptor
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p38 Mitogen-Activated Protein Kinases