Interleukin-18 as an in vivo mediator of monocyte recruitment in rodent models of rheumatoid arthritis.
BACKGROUND
The function of interleukin-18 (IL-18) was investigated in pertinent animal models of rodent rheumatoid arthritis (RA) to determine its proinflammatory and monocyte recruitment properties.


METHODS
We used a modified Boyden chemotaxis system to examine monocyte recruitment to recombinant human (rhu) IL-18 in vitro. Monocyte recruitment to rhuIL-18 was then tested in vivo by using an RA synovial tissue (ST) severe combined immunodeficient (SCID) mouse chimera. We defined monocyte-specific signal-transduction pathways induced by rhuIL-18 with Western blotting analysis and linked this to in vitro monocyte chemotactic activity. Finally, the ability of IL-18 to induce a cytokine cascade during acute joint inflammatory responses was examined by inducing wild-type (Wt) and IL-18 gene-knockout mice with zymosan-induced arthritis (ZIA).


RESULTS
We found that intragraft injected rhuIL-18 was a robust monocyte recruitment factor to both human ST and regional (inguinal) murine lymph node (LN) tissue. IL-18 gene-knockout mice also showed pronounced reductions in joint inflammation during ZIA compared with Wt mice. Many proinflammatory cytokines were reduced in IL-18 gene-knockout mouse joint homogenates during ZIA, including macrophage inflammatory protein-3alpha (MIP-3alpha/CCL20), vascular endothelial cell growth factor (VEGF), and IL-17. Signal-transduction experiments revealed that IL-18 signals through p38 and ERK1/2 in monocytes, and that IL-18-mediated in vitro monocyte chemotaxis can be significantly inhibited by disruption of this pathway.


CONCLUSIONS
Our data suggest that IL-18 may be produced in acute inflammatory responses and support the notion that IL-18 may serve a hierarchic position for initiating joint inflammatory responses.
Ruth
Jeffrey H
JH
Department of Internal Medicine, University of Michigan Medical School, 109 Zina Pitcher Drive, Ann Arbor, MI 48109, USA. jhruth@umich.edu
Park
Christy C
CC
Amin
M Asif
MA
Lesch
Charles
C
Marotte
Hubert
H
Shahrara
Shiva
S
Koch
Alisa E
AE
D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology*; D002465:Cell Movement / Q000502:physiology; D002633:Chemotaxis / Q000502:physiology; D002678:Chimera; D004195:Disease Models, Animal; D006801:Humans; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology; D013583:Synovial Membrane / Q000378:metabolism; D015054:Zymosan / Q000009:adverse effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D020382:Interleukin-18; D015054:Zymosan; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases