Complementary action of granulocyte-macrophage colony-stimulating factor and interleukin-17A induces interleukin-23, receptor activator of nuclear factor-kB ligand and matrix metalloproteinases and drives bone and cartilage pathology in experimental XXXX : rationale for combination therapy in rheumatoid arthritis.

@entity1 @entity2304 @entity32 @entity14293 @entity625 @entity19 @entity16 @entity1753 @entity5271 @entity79 @entity4155 @entity2720 @entity636
INTRODUCTION: T helper 17 (Th17) cells and @entity4155 play important roles in the pathogenesis of @entity1 and @entity19 @entity625 . Although there is a clear link between @entity636 and @entity2304 ( @entity2304 ) in the inflammatory cascade, details about their interaction in arthritic @entity2720 are unclear. In view of the introduction of @entity2304 - and @entity636 -inhibitors to the clinic, we studied how @entity636 and @entity2304 orchestrate the local production of inflammatory mediators during experimental @entity625 . METHODS: To allow detection of additive, complementary or synergistic effects of @entity636 and @entity2304 , we used two opposing experimental approaches: treatment of arthritic @entity19 with neutralising antibodies to @entity636 and @entity2304 , and local overexpression of these cytokines in na  ve @entity2720 . @entity19 were treated for two weeks with antibodies against @entity636 and/or @entity2304 after onset of @entity1753 ( @entity1753 ). Na  ve @entity19 were injected intra-articularly with adenoviral vectors for @entity636 and/or @entity2304 , resulting in local overexpression. Joint @entity32 was monitored by macroscopic scoring, X-ray and histology. Joint washouts, synovial cell- and lymph node cultures were analysed for cytokines, chemokines and inflammatory mediators by Luminex analysis, flow cytometry and quantitative polymerase chain reaction (QPCR). RESULTS: Combined therapeutic anti- @entity636 and anti- @entity2304 ameliorated @entity625 progression, and joint damage was dramatically reduced compared to treatment with anti- @entity636 or anti- @entity2304 alone. Anti- @entity636 specifically reduced synovial @entity14293 transcription, whereas anti- @entity2304 reduced transcription of matrix metalloproteinases (MMPs) and receptor activator of nuclear factor (NF)-kB ligand ( @entity5271 ). Overexpression of @entity636 or @entity2304 in naive knee joints elicited extensive inflammatory infiltrate, @entity16 and @entity79 . Combined overexpression revealed additive and synergistic effects on the production of MMPs, @entity5271 and @entity14293 in the synovium, and led to complete destruction of the joint structure within 7  days. CONCLUSIONS: @entity636 and @entity2304 differentially mediate the inflammatory process in @entity2720 , and show complementary and local additive effects. Combined blockade in arthritic @entity19 @entity16 not only by direct inhibition of @entity636 and @entity2304 , but also by indirect inhibition of @entity14293 and @entity5271 . Our results provide a rationale for combination therapy in auto-inflammatory conditions, especially for @entity1 that do not fully respond to inhibition of the separate cytokines.
