Secretory Leukocyte Protease Inhibitor Suppresses the Inflammation and Joint Damage of Bacterial Cell Wall–induced Arthritis

doi:10.1084/jem.190.4.535

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J. Exp. Med., Volume 190, Number 4, August 16, 1999 535-542
Copyright © 1999 by The Rockefeller University Press.

Secretory Leukocyte Protease Inhibitor Suppresses the Inflammation and Joint Damage of Bacterial Cell Wall–induced Arthritis

Xiao-yu Song^a, Li Zeng^a, Wenwen Jin^a, John Thompson^a, Diane E. Mizel^a, Ke-jian Lei^a, R.C. Billinghurst^b, A. Robin Poole^b, and Sharon M. Wahl^a
^a From the Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892-4352
^b Joint Diseases Laboratory, Shriners Hospitals for Children, Division of Surgical Research, Department of Surgery, McGill University, Montreal, Canada, H3G1A6

Correspondence to: Sharon M. Wahl, Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bldg. 30, Rm. 332, 30 Convent Dr., MSC 4352, Bethesda, MD 20892-4352. Tel:301-496-4178 Fax:301-402-1064 E-mail:smwahl{at}dir.nidcr.nih.gov.

Disruption of the balance between proteases and protease inhibitorsis often associated with pathologic tissue destruction. To explorethe therapeutic potential of secretory leukocyte protease inhibitor(SLPI) in erosive joint diseases, we cloned, sequenced, andexpressed active rat SLPI, which shares the protease-reactivesite found in human SLPI. In a rat streptococcal cell wall (SCW)-inducedmodel of inflammatory erosive polyarthritis, endogenous SLPIwas unexpectedly upregulated at both mRNA and protein levelsin inflamed joint tissues. Systemic delivery of purified recombinantrat SLPI inhibited joint inflammation and cartilage and bonedestruction. Inflammatory pathways as reflected by circulatingtumor necrosis factor ${alpha}$ and nuclear factor ${kappa}$ B activation and cartilageresorption detected by circulating levels of type II collagencollagenase-generated cleavage products were all diminishedby SLPI treatment in acute and chronic arthritis, indicatingthat the action of SLPI may extend beyond inhibition of serineproteases.

Key Words: inflammation, cartilage resorption, serine protease inhibitor

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