Synergistic benefit in inflammatory arthritis by targeting I kappaB kinase epsilon and interferon beta.
OBJECTIVE
The I kappaB kinase (IKK)-related kinase IKKepsilon regulates type I interferon expression and responses as well as proinflammatory mediator production. We examined the role of IKKepsilon in arthritis and its ability to enhance the therapeutic response to systemic interferon (IFN) beta therapy in passive murine K/BxN arthritis.


METHODS
IKKepsilon(-/-), IFN alpha(approximately)beta R(-/-) and wild type mice were given K/BxN serum and treated with polyinosinic polycytidylic acid (poly(I:C)), IFN beta, or normal saline. Clinical response and histological scores were assessed. Gene expression in the paws was measured by quantitative PCR. Serum interleukin 1a receptor agonist (IL1Ra) and IL10 were measured by ELISA and multiplex bead array.


RESULTS
Arthritis was almost completely blocked in wild type mice if arthritogenic K/BxN serum and the Toll-like receptor (TLR)3 ligand, poly(I:C), were coadministered at the onset of the model, but not in established disease. Mice deficient in IFN alpha(approximately)beta R had an accelerated course of arthritis, and did not respond to poly(I:C). IKKepsilon null mice had a modest decrease in clinical arthritis compared with heterozygous mice. Low doses of IFN beta that were ineffective in wild type mice significantly decreased clinical arthritis in IKKepsilon null mice. Articular chemokine gene expression was reduced in the IKKepsilon(-/-) mice with arthritis and secreted IL1Ra (sIL1Ra) mRNA was significantly increased. Serum levels of IL1Ra were increased in low dose IFN beta-treated IKKepsilon(-/-) mice.


CONCLUSIONS
Subtherapeutic doses of IFN beta enhance the anti-inflammatory effects of IKKepsilon deficiency, possibly by increasing production of IL1Ra and unmasking the antichemokine effects. Combination therapy with low dose IFN beta and an IKKepsilon inhibitor might improve efficacy of either agent alone and offers a novel approach to RA.
Corr
M
M
Division of Rheumatology, Allergy and Immunology, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0663, USA. mcorr@ucsd.edu
Boyle
D L
DL
Ronacher
L
L
Flores
N
N
Firestein
G S
GS
D000818:Animals; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical / Q000379:methods; D051550:I-kappa B Kinase / Q000172:deficiency / Q000502:physiology*; D007369:Interferon Inducers / Q000627:therapeutic use; D016899:Interferon-beta / Q000627:therapeutic use*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011070:Poly I-C / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use; D012720:Severity of Illness Index; D016896:Treatment Outcome
D018501:Antirheumatic Agents; D007369:Interferon Inducers; D053590:Interleukin 1 Receptor Antagonist Protein; D011994:Recombinant Proteins; D016899:Interferon-beta; D051550:I-kappa B Kinase; D011070:Poly I-C