Secretory leukocyte protease inhibitor suppresses the inflammation and joint damage of bacterial cell wall-induced arthritis.
Disruption of the balance between proteases and protease inhibitors is often associated with pathologic tissue destruction. To explore the therapeutic potential of secretory leukocyte protease inhibitor (SLPI) in erosive joint diseases, we cloned, sequenced, and expressed active rat SLPI, which shares the protease-reactive site found in human SLPI. In a rat streptococcal cell wall (SCW)-induced model of inflammatory erosive polyarthritis, endogenous SLPI was unexpectedly upregulated at both mRNA and protein levels in inflamed joint tissues. Systemic delivery of purified recombinant rat SLPI inhibited joint inflammation and cartilage and bone destruction. Inflammatory pathways as reflected by circulating tumor necrosis factor alpha and nuclear factor kappaB activation and cartilage resorption detected by circulating levels of type II collagen collagenase-generated cleavage products were all diminished by SLPI treatment in acute and chronic arthritis, indicating that the action of SLPI may extend beyond inhibition of serine proteases.
Song
X y
Xy
Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892-4352, USA.
Zeng
L
L
Jin
W
W
Thompson
J
J
Mizel
D E
DE
Lei
K
K
Billinghurst
R C
RC
Poole
A R
AR
Wahl
S M
SM
D000595:Amino Acid Sequence; D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy*; D001483:Base Sequence; D002473:Cell Wall; D003001:Cloning, Molecular; D005121:Extremities / Q000473:pathology; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism; D007596:Joints / Q000187:drug effects* / Q000473:pathology; D008969:Molecular Sequence Data; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000235:genetics / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins / Q000627:therapeutic use; D053481:Secretory Leukocyte Peptidase Inhibitor; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D015842:Serine Proteinase Inhibitors / Q000235:genetics / Q000627:therapeutic use*; D013297:Streptococcus pyogenes
D018836:Inflammation Mediators; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D011994:Recombinant Proteins; C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor; D015842:Serine Proteinase Inhibitors; C506816:Slpi protein, rat