Reduction of inflammatory cytokines and prostaglandin E2 by IL-13 gene therapy in rheumatoid arthritis synovium.
The rheumatoid arthritis (RA) joint is characterized by an inflammatory synovial pannus which mediates tissue destruction. IL-13 is a cytokine that inhibits activated monocytes/macrophages from secreting a variety of proinflammatory molecules. The aim of this study was to examine whether gene therapy-delivered IL-13 could reduce the production of key proinflammatory mediators in RA synovial tissue (ST) explants. Adenoviral vectors encoding the genes for human IL-13 (AxCAIL-13) and bacterial beta-galactosidase were generated and examined for protein production. Vectors were used to infect RA ST explants and RA synovial fibroblasts, and conditioned medium (CM) was collected at various times for analysis by ELISA and competitive immunoassay. AxCAIL-13 decreased the production of RA ST explant proinflammatory IL-1beta by 85% after 24 h. Likewise, TNF-alpha levels were decreased by 82 and 75% whereas IL-8 levels were reduced 54 and 82% after 24 and 48 h, respectively, in RA ST explant CM. Monocyte chemotactic protein-1 concentrations were decreased by 88% after 72 h in RA ST explant CM. RA ST explant epithelial neutrophil-activating peptide-78 concentrations were decreased 85 and 94% whereas growth-related gene product-alpha levels were decreased by 77 and 85% at 24 and 48 h, respectively, by AxCAIL-13. Further, IL-13 significantly decreased PGE2 and macrophage inflammatory protein-1alpha production. These results demonstrate that increased expression of IL-13 via gene therapy may decrease RA-associated inflammation by reducing secretion of proinflammatory cytokines and PGE2.
Woods
J M
JM
Department of Medicine, Northwestern University Medical School, Chicago, IL 60611, USA.
Katschke
K J
KJ
Tokuhira
M
M
Kurata
H
H
Arai
K I
KI
Campbell
P L
PL
Koch
A E
AE
D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000328:Adult; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000378:metabolism; D054360:Chemokine CXCL1; D054365:Chemokine CXCL5; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors / Q000378:metabolism; D002630:Chemotactic Factors / Q000037:antagonists & inhibitors / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000378:metabolism; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D015232:Dinoprostone / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000276:immunology / Q000494:pharmacology; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018793:Interleukin-13 / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D016209:Interleukin-8 / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000037:antagonists & inhibitors; D008297:Male; D008875:Middle Aged; D009924:Organ Culture Techniques; D011994:Recombinant Proteins / Q000494:pharmacology; D012995:Solubility; D013583:Synovial Membrane / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
C475829:CXCL1 protein, human; C486263:CXCL5 protein, human; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D054360:Chemokine CXCL1; D054365:Chemokine CXCL5; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D017077:Culture Media, Conditioned; D016207:Cytokines; D006133:Growth Substances; D018960:Hyaluronan Receptors; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1; D018793:Interleukin-13; D016209:Interleukin-8; D019402:Macrophage Inflammatory Proteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D015232:Dinoprostone