Antileukoproteinase: modulation of neutrophil function and therapeutic effects on anti-type II collagen antibody-induced arthritis.

Abstract

OBJECTIVE:

Antileukoproteinase (ALP) is a physiologic inhibitor of granulocytic serine proteases. The present study was undertaken to investigate its therapeutic benefit in an antibody-transfer model of erosive polyarthritis and to elucidate its potential to interfere with immune complex-dependent inflammatory pathways.

METHODS:

Arthritis development was induced in male (BALB/c x B10.Q)F(1) mice by intravenous injection of two monoclonal antibodies specific for type II collagen and was quantified by clinical scoring and histopathology. Arthritis severity was assessed in a cohort of mice under systemic treatment with recombinant human ALP (daily doses of 0.1 mg for 5 days starting immediately after disease induction) in comparison with untreated controls. Concomitantly, functional assays (phagocytosis, oxidative burst, fluorescence-activated cell sorting analysis of integrin expression) were performed on neutrophils upon in vitro stimulation by IgG-coated latex beads.

RESULTS:

ALP treatment reduced arthritis incidence and severity and had a protective effect against cartilage and bone erosion. ALP inhibited the conversion of the leukocyte beta2 integrins into an active conformation upon Fc receptor stimulation of granulocytes. ALP bound to the actin-bundling protein L-plastin and down-modulated filamentous actin assembly in response to stimulation with IgG-coated latex beads in granulocytes. ALP exerted additional inhibitory effects on neutrophil functions associated with cytoskeletal reorganization, such as phagocytosis and oxidative burst.

CONCLUSION:

In addition to its antiprotease activity, ALP exerts a variety of blocking effects on neutrophil functions, probably due to modulation of cytoskeletal changes, that may contribute to this inhibitor's antiarthritis potential and qualify it as a multifunctional regulator of inflammatory responses.

• Authors: Bettina Sehnert, Andrea Cavcic, Beate Böhm, Joachim R Kalden, Kutty Selva Nandakumar, Rikard Holmdahl, Harald Burkhardt
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 50 Issue 7 Pg. 2347-59 (Jul 2004) ISSN: 0004-3591 [Print] United States
• PMID: 15248236 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Antibodies, Monoclonal
• Collagen Type II
• Integrins
• Membrane Glycoproteins
• Microfilament Proteins
• Phosphoproteins
• Proteinase Inhibitory Proteins, Secretory
• Proteins
• Recombinant Proteins
• plastin

Topics

• Actins (chemistry, metabolism)
• Animals
• Antibodies, Monoclonal (immunology)
• Arthritis, Experimental (immunology, metabolism, pathology, physiopathology)
• Cell Membrane Permeability
• Collagen Type II (immunology)
• Cytosol (metabolism)
• Humans
• Integrins (metabolism)
• Joints (drug effects, pathology)
• Leukocytes (metabolism)
• Male
• Membrane Glycoproteins
• Mice
• Mice, Inbred Strains
• Microfilament Proteins (metabolism)
• Neutrophils (drug effects)
• Phagocytosis (drug effects)
• Phosphoproteins (metabolism)
• Proteinase Inhibitory Proteins, Secretory
• Proteins (pharmacology)
• Recombinant Proteins (pharmacology)
• Respiratory Burst (drug effects)
• Severity of Illness Index
• Up-Regulation (drug effects)