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Involvement
of Growth-Related Protein in Lipopolysaccharide-Induced Rabbit Arthritis:
Cooperation between Growth-Related Protein and IL-8, and Interrelated Regulation
among TNF[alpha], IL-1, IL-1 Receptor Antagonist, IL-8, and Growth-Related
Protein |
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Akihiro Matsukawa,
Teizo Yoshimura, Kazunori Fujiwara, Takako Maeda, Susumu Ohkawara, and Masaru
Yoshinaga |
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Department
of Pathology (AM, KF, TM, SO, MY), Kumamoto University School of Medicine,
Kumamoto, Japan; and Immunopathology Section (TY), Laboratory of Immunology,
National Cancer Institute, Frederick Cancer Research and Development Center,
Frederick, Maryland |
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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-TNF[alpha] mAb or anti-IL-8 IgG,
but reduced by rabbit recombinant IL-1 receptor antagonist (rrIL-1Ra) by
39%. The inhibition by rrIL-1Ra was augmented further to 59% with coadministered
anti-TNF[alpha] mAb. In contrast, the amounts of GRO at 9 hours were reduced
by rrIL-1Ra by 67%. There was no additional reduction in the amounts of
GRO at 9 hours by either combination of rrIL-1Ra with anti-TNF[alpha] mAb
or anti-IL-8 IgG. Administration of anti-GRO mAb did not alter TNF[alpha]
or IL-8 contents in SF at their peak (2 hours), but reduced the amounts
of IL-1[beta] 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-1[beta] and IL-1Ra, and (d) induction of GRO is not
regulated by IL-8. (Lab Invest, 79:591-600). |
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