Differential effects of anti-TNF-α and anti-IL-12/23 agents on human leukocyte-endothelial cell interactions.
Enhanced leukocyte recruitment is an inflammatory process that occurs during early phases of the vascular dysfunction that characterises atherosclerosis. We evaluated the impact of anti-TNF-α (adalimumab, infliximab and etanercept) and anti-IL-12/23 (ustekinumab) on interactions between human leukocytes and endothelial cells in a flow chamber that reproduced in vivo conditions. Clinical concentrations of anti-TNF-α were evaluated on the leukocyte recruitment induced by a variety of endothelial (TNF-α, interleukin-1β, lymphotoxin-α and angiotensin-II) and leukocyte (PAF, IL-12 and IL-23) stimuli related to inflammation and atherosclerosis. Treatment with anti-TNF-α, even before or after establishing the inflammatory situation induced by TNF-α, diminished leukocyte-endothelial cell interactions induced by this stimuli. Our results also implicated adhesion molecules (ICAM-1, VCAM-1 and E-selectin) in the actions of anti-TNF-α in terms of leukocyte adhesion to endothelium. However, anti-TNF-α drugs did not influence the actions of interleukin-1β, but prevented those of lymphotoxin-α and angiotensin-II. However, once established, inflammatory response elicited by the latter three stimuli could not be reversed. Pre-treatment with anti-TNF-α, also prevented leukocyte actions induced by IL-23 on PBMC rolling flux and rolling velocity and by IL-12 on PMN adhesion. Ustekinumab exhibited a more discreet profile, having no effect on leukocyte recruitment induced by any of the endothelial stimuli, while blocking the effects of IL-23 on leukocyte activation and those of IL-12 on PMN adhesion and PAF on PBMC rolling velocity. These findings endorse the idea that biological anti-inflammatory drugs, in particular anti-TNF-α, have the capacity to influence cardiovascular risk accompanying psoriasis and rheumatoid arthritis by ameliorating vascular inflammation.
Departamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; FISABIO- Hospital Universitario Dr. Peset, Valencia, Spain. Electronic address: cesar.rios@uv.es.
Cesar
C
Ríos-Navarro
Departamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Valencia, Spain. Electronic address: carmen.pablo@uv.es.
Carmen
C
de Pablo
Departamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; FISABIO- Hospital Universitario Dr. Peset, Valencia, Spain. Electronic address: victor.collado@uv.es.
Víctor
V
Collado-Diaz
Departamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; FISABIO- Hospital Universitario Dr. Peset, Valencia, Spain. Electronic address: samuel.orden@uv.es.
Samuel
S
Orden
Departamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; FISABIO- Hospital Universitario Dr. Peset, Valencia, Spain. Electronic address: ana.blas@uv.es.
Ana
A
Blas-Garcia
Departamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Valencia, Spain. Electronic address: angeles.martinez@uv.es.
María Ángeles
MÁ
Martínez-Cuesta
Departamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; FISABIO- Hospital Universitario Dr. Peset, Valencia, Spain. Electronic address: juan.v.esplugues@uv.es.
Juan V
JV
Esplugues
Departamento de Farmacología and CIBERehd, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; Fundación General Universidad de Valencia, Valencia, Spain. Electronic address: angeles.alvarez@uv.es.
Angeles
A
Alvarez
D000068879:Adalimumab / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D053759:Interleukin-23 / Q000037:antagonists & inhibitors*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D053759:Interleukin-23; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D000068879:Adalimumab
Anti-IL-12/23 agents; Anti-TNF-α agents; Biologics; Cardiovascular side effects; Leukocyte–endothelial cell interactions; Rheumatic diseases