Abstract
PGRN was previously reported to bind to TNF receptors (TNFR) and is therapeutic against inflammatory arthritis. Here we present further evidences demonstrating the PGRN inhibition of TNF-alpha binding and activity, and clarifying the distinct mechanisms underlying TNF-alpha inhibition between PGRN and classic TNF-alpha-binding inhibitors. In addition, we present evidences indicating that three TNFR binding domains of PGRN act independently in binding to TNFR. Furthermore, changing the order of three TNFR-binding domains in Atsttrin, a PGRN-derived molecule composed of these TNFR-binding domains, does not affect its anti-inflammatory and anti-TNF activities in both collagen-induced inflammatory arthritis and human TNF-alpha transgenic mouse model. Taken together, these findings provide the additional molecular basis underlying PGRN/TNFR interaction and PGRN-mediated anti-inflammatory activity in various inflammatory diseases and conditions.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Arthritis, Experimental / prevention & control
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Binding Sites / genetics
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Cell Line
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Cell Line, Tumor
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Cell Membrane / metabolism
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Cells, Cultured
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Gene Expression / drug effects
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HEK293 Cells
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Humans
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Intercellular Adhesion Molecule-1 / genetics
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism*
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Intercellular Signaling Peptides and Proteins / pharmacology
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Macrophages / drug effects
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Macrophages / metabolism
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Male
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Mice, Inbred C57BL
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Mice, Inbred DBA
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Mice, Transgenic
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Progranulins
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Protein Binding / drug effects
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Receptors, Tumor Necrosis Factor / genetics
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Receptors, Tumor Necrosis Factor / metabolism*
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Recombinant Proteins / pharmacology
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Reverse Transcriptase Polymerase Chain Reaction
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism*
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Tumor Necrosis Factor-alpha / pharmacology
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Two-Hybrid System Techniques
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Vascular Cell Adhesion Molecule-1 / genetics
Substances
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GRN protein, human
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Intercellular Signaling Peptides and Proteins
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Progranulins
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Receptors, Tumor Necrosis Factor
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Recombinant Proteins
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Tumor Necrosis Factor-alpha
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Vascular Cell Adhesion Molecule-1
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Intercellular Adhesion Molecule-1