IL‐6, but not IL‐4, stimulates chemokinesis and TNF stimulates chemotaxis of tissue mast cells: involvement of both mitogen‐activated protein kinases and phosphatidylinositol 3‐kinase signalling pathways

Abstract

An increase in the number of mast cells within tissues is observed in many pathophysiological conditions. Current data indicate that migration of mature mast cells might be one of the key mechanisms responsible for rapid local accumulation of these cells. Considering that interleukin (IL)-6 and IL-4, as well as tumour necrosis factor (TNF), influence mast cell activity in various ways, the purpose of the current study was to examine whether these cytokines function as rat peritoneal mast cell chemoattractants. We showed that IL-4, in the concentration range from 10(-6) to 10(-3) ng/ml, did not induce a mast cell migratory response, even in the presence of laminin and fibronectin. Under the same experimental conditions, mast cells were shown to migrate in response to IL-6 stimulation in the presence of laminin. The optimal concentration of IL-6 for maximal migration of mast cells was 10(-4) ng/ml (i.e. approximately 5 nM). In comparison, the optimal concentration of TNF for maximal migration of mast cells was 5 x 10(-5) ng/ml (i.e. approximately 3 fM). IL-6-stimulated mast cell migration was the result of chemokinesis, whereas TNF-induced migration was the result of chemotaxis. Mast cell migratory responses to IL-6 and TNF were entirely blocked by specific anti-IL-6R and anti-TNFR1 antibodies. We also documented that the migration response of mast cells to stimulation with IL-6 and TNF was mediated through signal transduction pathways involving mitogen-activated protein kinases and phosphatidylinositol 3-kinase. Taken together, our results indicate that IL-6, as well as TNF, induces tissue mast cell migration. Thus, these proinflammatory cytokines can be responsible for mast cell accumulation at the site of diverse conditions accompanied by inflammation.

Role of interleukin-18 in the pathophysiology of allergic diseases

“…The ability of basophils to independently recruit eosinophils and neutrophils in chronic allergic inflammation was demonstrated in a mouse model, and the low abundance (<2%) of basophils in the infiltrates suggested that basophils initiate rather than effect chronic inflammation [33]. In addition, mast cells have the ability to secrete serotonin, enzymes like chymase and tryptase, peptides, growth factors, cytokines, and chemokines, which act as powerful chemoattractants, regulate migration of mast cells, and activate platelets, among many other effects [34–37]. Important cytokines produced by both mast cells and basophils include thymic stromal lymphopoetin (TSLP), IL-4, IL-5, IL-13, IL-25, and granulocyte/macrophage colony stimulating factor (GM-CSF) [38–42].…”

IL-6 promotes an increase in human mast cell numbers and reactivity through suppression of suppressor of cytokine signaling 3

“…1, 2 These include the clinical observations that IL-6 levels relate to the severity of disease in systemic mastocytosis 3, 4 acute 5 and chronic urticaria, 6 and asthma. 7 In vitro, IL-6 promotes HuMC maturation, 8 adhesion to extracellular matrix, 9 chemokinesis, 10 and survival, the latter through IgE dependent production of mast cell derived IL-6. 11 IL-6 is also routinely used to supplement stem cell factor (SCF) to generate HuMCs from cord or peripheral blood progenitor (CD34 + ) cells.…”

Evaluation of Moon-tang on allergic reactions

“…(30) In addition, TNF-α is known as a target cytokine in therapy of allergic disease, inflammatory, and immune disease because the mast cell is the only known cell to prestore TNF-α and is able to release this mediator immediately upon activation. (31,32) In current study, M-tang treatment induced significantly the inhibitory effect on the PMA plus A23187-induced secretion and expression of TNF-α. These data also indicate that M-tang has the effective anti-inflammatory as a result of its reduction of TNF-α production in mast cells.…”