Heat shock protein 10 inhibits lipopolysaccharide-induced inflammatory mediator production.
Heat shock protein 10 (Hsp10) and heat shock protein 60 (Hsp60) were originally described as essential mitochondrial proteins involved in protein folding. However, both proteins have also been shown to have a number of extracellular immunomodulatory activities. Here we show that purified recombinant human Hsp10 incubated with cells in vitro reduced lipopolysaccharide (LPS)-induced nuclear factor-kappaB activation and secretion of several inflammatory mediators from RAW264.7 cells, murine macrophages, and human peripheral blood mononuclear cells. Induction of tolerance by contaminating LPS was formally excluded as being responsible for Hsp10 activity. Treatment of mice with Hsp10 before endotoxin challenge resulted in the reduction of serum tumor necrosis factor-alpha and RANTES (regulated upon activation, normal T cell expressed and secreted) levels and an elevation of serum interleukin-10 levels. Hsp10 treatment also delayed mortality in a murine graft-versus-host disease model, where gut-derived LPS contributes to pathology. We were unable to confirm previous reports that Hsp10 has tumor growth factor properties and suggest that Hsp10 exerts anti-inflammatory activity by inhibiting Toll-like receptor signaling possibly by interacting with extracellular Hsp60.
Johnson
Barbara J
BJ
CBio Limited, 17 Wakefield St., Alderley, Queensland 4051, Australia. barbara.johnson@cbio.com.au
Le
Thuy T T
TT
Dobbin
Caroline A
CA
Banovic
Tatjana
T
Howard
Christopher B
CB
Flores
Flor de Maria Leon
Fde M
Vanags
Daina
D
Naylor
Dean J
DJ
Hill
Geoffrey R
GR
Suhrbier
Andreas
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D001681:Biological Assay; D016026:Bone Marrow Transplantation; D002460:Cell Line; D049109:Cell Proliferation; D018835:Chaperonin 10 / Q000502:physiology*; D018834:Chaperonin 60 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007249:Inflammation; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D020014:K562 Cells; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008070:Lipopolysaccharides / Q000737:chemistry / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000378:metabolism; D011485:Protein Binding; D017510:Protein Folding; D011994:Recombinant Proteins / Q000737:chemistry; D015398:Signal Transduction; D013997:Time Factors; D014357:Trypsin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D020298:U937 Cells
D000911:Antibodies, Monoclonal; D018835:Chaperonin 10; D018834:Chaperonin 60; D018946:Chemokine CCL5; D004731:Endotoxins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D014357:Trypsin