Mechanism of Action of Methotrexate: Experimental Evidence that Methotrexate Blocks the Binding of Interleukin 1β to the Interleukin 1 Receptor on Target Cells

Abstract

Interleukin 1, a multifunctional cytokine, plays a central role in inflammatory processes and induction of the immune response. Target cells possess 200 -5000 (or more) interleukin 1 receptors per cell, but they exhibit a full biological response when only 1 -2% of these receptors are occupied by interleukin la or I . Methotrexate has been reported to be beneficial in several inflammatory and autoimmune diseases. On the other hand, many of these diseases are known to share an overproduction of interleukin 1. It has been demonstrated that methotrexate has no influence on the interleukin 1 synthesis, so we focused our attention on the ability of methotrexate to interfere with the binding of interleukin 1 β to the interleukin 1 receptor. The experiments were performed on monocytes, lymphocytes and granulocytes using a recombinant human cytokine probe. Methotrexate led to an astonishing decrease in the binding of interleukin 1 β to the interleukin 1 receptor of peripheral blood cells, whereas methylprednisolone and indomethacin were not inhibitory. The inhibitory effect of methotrexate was dose dependent. An excess of interleukin I abolished the inhibition of cytokine binding by methotrexate. We also demonstrated that methotrexate does not affect the integrity of the interleukin 1 receptor or of the target cells. Our results demonstrate that methotrexate blocks the interleukin l -interleukin 1 receptor pathway. Methotrexate is therefore another interleukin 1 inhibitor and a clinically efficient anticytokine. but exert a full biological effect when only 1 -2% of Interleukin 1 is represented by two distinct cytokines, these receptors are occupied by interleukin 1 (2). interleukin la and interleukin I polypeptides, which ^ ,11·,.,

Molecular targets in arthritis and recent trends in nanotherapy

“…7 Other multiple mechanisms are involved apart from the inhibition of dihydrofolate reductase that include inhibition of 1) enzymes that play a role in purine metabolism 8 and 2) binding of IL-1 beta to its cell-surface receptor. 9 Some of the commonly associated side effects of using MTX are ulcerative stomatitis, liver damage (hepatotoxicity), low count of white blood cells, which further lead to nausea, abdominal pain, fever, fatigue, infection, dizziness, and acute pneumonitis. In a few cases, it rarely leads to pulmonary fibrosis.…”

Low-Dose Methotrexate Controls a Severe Form of Polyarteritis Nodosa

“…10,11 Previously, we demonstrated in an in vitro assay that methotrexate inhibited IL-1␤ binding to its cell surface receptor. 12 Interleukin 1 plays a central role in inflammatory events and vasculitides. It activates endothelial cells to express adhesion molecules and to produce other pro-inflammatory cytokines, such as IL-6 and IL-8, and stimulates the chemotactic activity of neutrophils.…”

Use of Methotrexate in Patients With Calcium Pyrophosphate Crystal Deposition Disease

“…К теоретическим предпосылкам более широкого использования МТ следует отнести, во-первых, нали-чие у препарата, помимо других механизмов действия, способности к ингибированию связывания интерлей-кина 1β (ИЛ1β) с его рецептором на клеточной поверх-ности [13], что может быть принципиально важно, так как молекулярные процессы ПФК-индуцированного воспаления заключаются в активации NALP3 инфлам-масомы, в конечном итоге приводящей к гиперпродук-ции ИЛ1β, ключевого цитокина в развитии воспаления при микрокристаллических артритах [14]. Во-вторых, благоприятное влияние на риск сердечно-сосудистых событий и смертности, что доказано у пациентов с РА и предполагается на популяционном уровне [15,16].…”