Critical role of extracellular vesicles in modulating the cellular effects of cytokines.
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.
Department of Genetics, Cell- and Immunobiology, Semmelweis University, Budapest, Hungary.
Géza Tamás
GT
Szabó
Bettina
B
Tarr
Krisztina
K
Pálóczi
Katalin
K
Éder
Eszter
E
Lajkó
Ágnes
Á
Kittel
Sára
S
Tóth
Bence
B
György
Mária
M
Pásztói
Andrea
A
Németh
Xabier
X
Osteikoetxea
Éva
É
Pállinger
András
A
Falus
Katalin
K
Szabó-Taylor
Edit Irén
EI
Buzás
D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000378:metabolism; D016000:Cluster Analysis; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D055354:Exosomes / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D018932:Chemokine CCL2; D016207:Cytokines; D016209:Interleukin-8; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha