Selective, α2β1 Integrin-Dependent Secretion of IL-6 by Connective Tissue Mast Cells

McCall-Culbreath, Karissa D.; Li, Zhengzhi; Zhang, Zhonghua; Lu, Lucy X.; O'Rear, Lynda; Zutter, Mary M.

doi:10.1159/000324832

Cited by 15 publications

(15 citation statements)

References 61 publications

(67 reference statements)

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“…Nishida et al [67•] demonstrated that the presence of Gab2 affects mast cell degranulation, but not cytokine production, and demonstrated different requirements for the development of IgE-mediated anaphylaxis versus contact hypersensitivity. Differential regulation of mast cell degranulation and cytokine production, specifically IL-6, with distinct stimuli, resulting in the release of specific mediator pools, has also been demonstrated by McCallCulbreath et al [68].…”

Section: Regulation Of Fcεri Signalling Mast Cell Function and Medimentioning

confidence: 64%

Mediators Released During Human Anaphylaxis

Stone

Brown

2011

Curr Allergy Asthma Rep

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A range of mediators are generated during anaphylaxis, with redundancy of effects, multiple overlapping pathways, and involvement of several cell types. Key steps in the reaction occur at the site of initial contact, and mediators may not be detectable systemically. Furthermore, the potencies of various mediators vary enormously, and clinical effects may occur below our level of detection. We also do not know what converts (amplifies) a local reaction into systemic anaphylaxis. Murine models have identified several novel mediators that may propagate and/or regulate this process and also indicate that circulating neutrophils may play an important role in reaction amplification. Differential expression of various genes within specific intracellular signalling pathways of mediator release may further explain the varying severities of anaphylactic reactions. As our knowledge of the mechanisms of activation, key mediators, and the regulation of mediator release improves, new treatments for prevention and acute management may emerge.

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Section: Regulation Of Fcεri Signalling Mast Cell Function and Medimentioning

confidence: 64%

Mediators Released During Human Anaphylaxis

Stone

Brown

2011

Curr Allergy Asthma Rep

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“…L. monocytogenes and specifically the pore-forming toxin LLO [23], cause mast cell degranulation in vivo [24] and in vitro [3]. Mast cells have also been shown to release cytokines directly in response to L. monocytogenes under various conditions [6], [7], [9], [10], [24]. We therefore focused on further investigating the effect of L. monocytogenes on mast cell activation, specifically mast cell degranulation and mediator release.…”

Section: Resultsmentioning

confidence: 99%

“…During degranulation, pre-formed tumour necrosis factor-α (TNF-α) is released resulting in the recruitment and activation of neutrophils [3], [6]. TNF-α, however, is just one of the cytokines released in response to L. monocytogenes with other pro-inflammatory cytokines, including IL-6 and IL-1β, released during infection in vivo [7], [8], and mast cells have been shown to secrete these in response to L. monocytogenes in vitro [7], [9], [10].…”

Section: Introductionmentioning

confidence: 99%

Listeria monocytogenes Alters Mast Cell Phenotype, Mediator and Osteopontin Secretion in a Listeriolysin-Dependent Manner

et al. 2013

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Whilst mast cells participate in the immune defence against the intracellular bacterium Listeria monocytogenes, there is conflicting evidence regarding the ability of L. monocytogenes to infect mast cells. It is known that the pore-forming toxin listeriolysin (LLO) is important for mast cell activation, degranulation and the release of pro-inflammatory cytokines. Mast cells, however, are a potential source of a wide range of cytokines, chemokines and other mediators including osteopontin, which contributes to the clearing of L. monocytogenes infections in vivo, although its source is unknown. We therefore aimed to resolve the controversy of mast cell infection by L. monocytogenes and investigated the extent of mediator release in response to the bacterium. In this paper we show that the infection of bone marrow-derived mast cells by L. monocytogenes is inefficient and LLO-independent. LLO, however, is required for calcium-independent mast cell degranulation as well as for the transient and selective downregulation of cell surface CD117 (c-kit) on mast cells. We demonstrate that in addition to the key pro-inflammatory cytokines TNF-α and IL-6, mast cells release a wide range of other mediators in response to L. monocytogenes. Osteopontin, IL-2, IL-4, IL-13 and granulocyte macrophage colony-stimulating factor (GM-CSF), and chemokines including CCL2, CCL3, CCL4 and CCL5 are released in a MyD88-dependent manner. The wide range of mediators released by mast cells in response to L. monocytogenes may play an important role in the recruitment and activation of a variety of immune cells in vivo. The cocktail of mediators, however, is unlikely to skew the immune response to a particular effector response. We propose that mast cells provide a hitherto unreported source of osteopontin, and may provide an important role in co-ordinating the immune response during Listeria infection.

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“…In addition, previous studies and recent evidence from the a2b1 integrin-deficient mice indicated that although osteoclasts may express a2b1 integrin, it seems that their function depends more on avb3 integrin rather than on a2b1 and other integrins (43,44). In contrast, a2b1 integrin has been shown to regulate mast cell activation (45,46), and mast cells have been associated with the pathogenesis of arthritis (47). Although mast cells are not required in the model of CIA used in this study (48), the earlier findings suggest that a2 integrin blockade can also affect mast cell activity during the course of arthritis and, therefore, contribute to the reduction of arthritis severity.…”

Section: Discussionmentioning

confidence: 99%

α2β1 Integrin Regulates Th17 Cell Activity and Its Neutralization Decreases the Severity of Collagen-Induced Arthritis

Azreq

Boisvert

Césaro

et al. 2013

The Journal of Immunology

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Th17 cells play a critical role in the pathogenesis of rheumatoid arthritis (RA), but the mechanisms by which these cells regulate the development of RA are not fully understood. We have recently shown that α2β1 integrin, the receptor of type I collagen, is the major collagen-binding integrin expressed by human Th17 cells. In this study, we examined the role of α2β1 integrin in Th17-mediated destructive arthritis in the murine model of collagen-induced arthritis (CIA). We found that α2β1 integrin is expressed on synovial Th17 cells from CIA mice and its neutralization with a specific mAb significantly reduced inflammation and cartilage degradation, and protected the mice from bone erosion. Blockade of α2β1 integrin led to a decrease in the number of Th17 cells in the joints and to a reduction of IL-17 levels in CIA mice. This was associated with an inhibition of receptor activator of NF-κB ligand levels and osteoclast numbers, and reduction of bone loss. We further show that α2β1 integrin is expressed on synovial Th17 cells from RA patients, and that its ligation with collagen costimulated the production of IL-17 by polarized human Th17 cells by enhancing the expression of retinoic acid receptor–related orphan receptor C through ERK and PI3K/AKT. Our findings provide the first evidence, to our knowledge, that α2β1 integrin is an important pathway in Th17 cell activation in the pathogenesis of CIA, suggesting that its blockade can be beneficial for the treatment of RA and other Th17-associated autoimmune diseases.

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Selective, α2β1 Integrin-Dependent Secretion of IL-6 by Connective Tissue Mast Cells

Cited by 15 publications

References 61 publications

Mediators Released During Human Anaphylaxis

Mediators Released During Human Anaphylaxis

Listeria monocytogenes Alters Mast Cell Phenotype, Mediator and Osteopontin Secretion in a Listeriolysin-Dependent Manner

α2β1 Integrin Regulates Th17 Cell Activity and Its Neutralization Decreases the Severity of Collagen-Induced Arthritis

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