IL-4 Adenoviral Gene Therapy Reduces Inflammation, Proinflammatory Cytokines, Vascularization, and Bony Destruction in Rat Adjuvant-Induced Arthritis

Abstract

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-α, IL-1β, 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.

Intra-articular lentivirus-mediated delivery of galectin-3 shRNA and galectin-1 gene ameliorates collagen-induced arthritis

“…44 Upon sacrifice on day 18, rat ankles were removed and immediately put on ice, and then radiographic examinations were performed. Radiographs were scored on the joint space change, degree of bony destruction and the soft tissue swelling, and all scores were summed up with a total scale from 0 to 10.…”

“…Radiographs were scored on the joint space change, degree of bony destruction and the soft tissue swelling, and all scores were summed up with a total scale from 0 to 10. 44 …”

Anti-Inflammatory Cytokines in Sepsis: Immunological Studies and In Silico Investigation

“…Endogenous IL-4 is thought to inhibit development of arthritis, but it has not been proven to present this effect [21]. Studies performed with a group of trauma victims showed a possible correlation between IL-4/-589 polymorphism and its stimulating action on the Th2 immune response, with development of a severe picture of systemic inflammatory response in these subjects.…”

“…It is produced and regulated mainly by Th2 cells, mast cells, and basophils. In vitro experiments have shown that IL-4 acts on monocytes, inhibiting production of inflammatory cytokines, such as TNF-a, IL-1a, IL-1b, IL-6, and IL-8 [21]. Its protective antiinflammatory effect in chronic illness -such as diabetes mellitus and rheumatoid arthritis -is being investigated, opening possibilities for its role as a potential factor in the treatment of auto-immune diseases [21][22].…”

Prothymosin α Lacking the Nuclear Localization Signal as an Effective Gene Therapeutic Strategy in Collagen-Induced Arthritis

“…Synovial tissues taken from the ankle joints of rats with CIA on day 27 were snap frozen and homogenized, as described previously (32). The levels of MIP-1␣, IL-1␤, and TNF-␣ in the ankle homogenates were quantified using ELISA kits (R&D Systems), according to the manufacturer's instructions.…”