Under physiological and pathological conditions, extracellular vesicles (EVs) are
present in the extracellular compartment simultaneously with soluble mediators. We
hypothesized that cytokine effects may be modulated by EVs, the recently recognized
conveyors of intercellular messages. In order to test this hypothesis, human monocyte
cells were incubated with CCRF acute lymphoblastic leukemia cell line-derived EVs
with or without the addition of recombinant human TNF, and global gene expression
changes were analyzed. EVs alone regulated the expression of numerous genes related
to inflammation and signaling. In combination, the effects of EVs and TNF were additive,
antagonistic, or independent. The differential effects of EVs and TNF or their simultaneous
presence were also validated by Taqman assays and ELISA, and by testing different
populations of purified EVs. In the case of the paramount chemokine IL-8, we were
able to demonstrate a synergistic upregulation by purified EVs and TNF. Our data suggest
that neglecting the modulating role of EVs on the effects of soluble mediators may
skew experimental results. On the other hand, considering the combined effects of
cytokines and EVs may prove therapeutically useful by targeting both compartments
at the same time.
