IL-4 adenoviral gene therapy reduces inflammation, proinflammatory cytokines, vascularization, and bony destruction in rat adjuvant-induced arthritis.
IL-4 is a cytokine with anti-inflammatory properties on activated macrophages. Rheumatoid arthritis, an autoimmune inflammatory disease, is characterized by a paucity of IL-4 and an abundance of synovial macrophage-derived mediators. Herein, the effect of a single injection of adenovirus-producing rat IL-4 (AxCAIL-4) or a control virus with no inserted gene was compared with the effect of PBS injection into rat ankles. Ankles were injected before arthritis onset or at maximal inflammation. Preventatively, AxCAIL-4 reduced adjuvant-induced arthritis (AIA)- and/or AIA/adenoviral-induced ankle inflammation, decreasing articular index scores, ankle circumferences, paw volumes, radiographic scores, mean levels of monocyte chemoattractant protein-1, the number of inflammatory cells, and the number of synovial blood vessels. Therapeutically, AxCAIL-4 also decreased ankle circumferences and paw volumes in comparison with a control virus with no inserted gene and PBS groups. After arthritis onset, mean levels of TNF-alpha, IL-1beta, macrophage inflammatory protein-2, and RANTES were decreased in AxCAIL-4 rat ankle homogenates compared with PBS-treated homogenates. Thus, increased expression of IL-4 via gene therapy administered in a preventative and/or therapeutic manner reduced joint inflammation, synovial cellularity, levels of proinflammatory cytokines, vascularization, and bony destruction in rat AIA, suggesting that a similar treatment in humans may be beneficial.
Woods
J M
JM
Departments of. Medicine and Pathology, Northwestern University Medical School, Chicago, IL 60611, USA.
Katschke
K J
KJ
Volin
M V
MV
Ruth
J H
JH
Woodruff
D C
DC
Amin
M A
MA
Connors
M A
MA
Kurata
H
H
Arai
K
K
Haines
G K
GK
Kumar
P
P
Koch
A E
AE
D000260:Adenoviruses, Human / Q000235:genetics* / Q000276:immunology; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D001862:Bone Resorption / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D002645:Chickens; D016207:Cytokines / Q000037:antagonists & inhibitors*; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology; D006614:Hindlimb; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors*; D007270:Injections, Intra-Articular; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics*; D016254:Mutagenesis, Insertional / Q000379:methods; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D051381:Rats; D011917:Rats, Inbred Lew; D010948:Viral Plaque Assay / Q000379:methods
D016207:Cytokines; D018836:Inflammation Mediators; D015847:Interleukin-4