Homing chemokines in rheumatoid arthritis

In about 20% of patients with rheumatoid arthritis, B and T lymphocytes recruited into the inflamed synovium are organized into complex microstructures, which resemble secondary lymphoid organs. The development of such lymphoid aggregates with germinal centers appears to contribute to the pathogenesis of the disease. Growing evidence indicates that chemokines and their receptors control the recruitment and positioning of leukocytes as well as their organization into node-like lymphoid structures. Here, we comment on recent studies highlighting the importance of chemokines in rheumatoid arthritis, in particular of B-cell-activating chemokine-1 in lymphoid neogenesis in the inflamed synovium.     

IL-3 and IL-5 prime normal human eosinophils to produce leukotriene C4 in response to soluble agonists

Eosinophils (Eos) produce large amounts of leukotriene C4 (LTC4) and platelet-activating factor (PAF) in response to calcium ionophore. However, the capacity of naturally occurring soluble agonists to promote lipid mediator formation by Eos is largely unknown. Our previous studies on neutrophils and basophils showed that certain hematopoietic growth factors are important regulators of lipid mediator formation. We examined LTC4 production by normal human Eos from healthy donors in response to soluble agonists with or without preincubation with the cytokines IL-3 and IL-5. Among three agonists (FMLP, C5a, PAF) tested over a wide concentration range, only FMLP induced some LTC4 formation by itself in normal Eos. However, after preincubation with IL-3 or IL-5, Eos produced detectable amounts of LTC4 in response to all three agonists. Eos primed by IL-3 or IL-5 generated at least 1 order of magnitude more LTC4 in response to FMLP as compared to C5a or PAF. FMLP-induced LTC4 production was enhanced by 26 to 635% (n = 16) and 67 to 611% (n = 12) after preincubation with IL-3 or IL-5, respectively. Priming for LTC4 production was concentration dependent occurring at IL-3 or IL-5 concentrations of 3 to 30 ng/ml and required an optimal preincubation period of 90 min. Thus, IL-3 and IL-5 profoundly modulate the production of lipid mediators by Eos in response to the soluble agonists FMLP, C5a, and PAF. Our data further support the importance of these cytokines in inflammatory reactions involving Eos.