Involvement of growth-related protein in lipopolysaccharide-induced rabbit arthritis: cooperation between growth-related protein and IL-8, and interrelated regulation among TNFalpha, IL-1, IL-1 receptor antagonist, IL-8, and growth-related protein

Lab Invest. 1999 May;79(5):591-600.


We investigated the functional role of a CXC chemokine, growth-related protein (GRO), in the recruitment of neutrophils in lipopolysaccharide (LPS)-induced rabbit arthritis. The amounts of GRO in the synovial fluids (SF) reached the first peak (major) at 2 hours and the second peak (minor) at 9 hours after injection of LPS into the knee joints. Administration of anti-GRO mouse monoclonal antibody inhibited 54% of the peak leukocyte accumulation at 9 hours (neutrophils greater than 95%), which was similar to the inhibition by anti-IL-8 IgG (48%). Co-administration of these inhibitors increased the inhibition up to 70% at 9 hours and also inhibited 65% of the initial phase of leukocyte infiltration at 2 hours (neutrophils greater than 99%), which was not affected by a single administration of each inhibitor. The amounts of GRO in SF at 2 hours were not altered by either anti-TNFalpha mAb or anti-IL-8 IgG, but reduced by rabbit recombinant IL-1 receptor antagonist (rrlL-1Ra) by 39%. The inhibition by rrlL-1 Ra was augmented further to 59% with coadministered anti-TNFalpha mAb. In contrast, the amounts of GRO at 9 hours were reduced by rrlL-1Ra by 67%. There was no additional reduction in the amounts of GRO at 9 hours by either combination of rrlL-1Ra with anti-TNFalpha mAb or anti-IL-8 IgG. Administration of anti-GRO mAb did not alter TNFalpha or IL-8 contents in SF at their peak (2 hours), but reduced the amounts of IL-1beta at 6 hours and IL-1Ra at 9 hours by 42% and 49%, respectively. These results provide evidence for the following: (a) GRO as well as IL-8 are important mediators involved in the recruitment of neutrophils both in the early and the late phase of LPS-induced arthritis, (b) IL-1 produced in the early phase stimulates GRO production, (c) GRO plays a role in the later induction of IL-1beta and IL-1Ra, and (d) induction of GRO is not regulated by IL-8.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / biosynthesis
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology
  • Arthritis / chemically induced
  • Arthritis / metabolism*
  • Cell Line
  • Chemokines, CXC / genetics
  • Chemokines, CXC / immunology
  • Chemokines, CXC / physiology*
  • Fluoroimmunoassay
  • Growth Substances / genetics
  • Growth Substances / immunology
  • Growth Substances / physiology*
  • Immunoglobulin G / immunology
  • Immunohistochemistry
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1 / metabolism
  • Interleukin-8 / immunology
  • Interleukin-8 / metabolism
  • Leukocyte Count
  • Lipopolysaccharides / pharmacology*
  • Mice
  • Mice, Inbred BALB C
  • Neutrophils / cytology
  • Neutrophils / drug effects
  • Neutrophils / immunology
  • Rabbits
  • Recombinant Proteins / genetics
  • Recombinant Proteins / immunology
  • Sialoglycoproteins / immunology
  • Sialoglycoproteins / metabolism
  • Synovial Fluid / chemistry
  • Synovial Fluid / drug effects
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / metabolism


  • Antibodies, Monoclonal
  • Chemokines, CXC
  • Growth Substances
  • Il1rn protein, mouse
  • Immunoglobulin G
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1
  • Interleukin-8
  • Lipopolysaccharides
  • Recombinant Proteins
  • Sialoglycoproteins
  • Tumor Necrosis Factor-alpha