Transcriptional Response Of Human Mast Cells Stimulated Via The Fc Epsilon;RI And Identification Of Mast Cells As A Source Of IL-11
Sayama K, Diehn M, Matsuda K, Lunderius C, Tsai M, Tam SY, Botstein D, Brown PO, Galli SJ
BMC Immunol 2002 Jun 12;3(1):5
Stanford University School of Medicine, Department of Pathology, Stanford, California, USA
In Asthma and other Allergic Disorders, the activation of Mast Cells by IgE and Antigen induces the cells to release Histamine and other mediators of inflammation, as well as to produce certain Cytokines and Chemokines.
To search for new Mast Cell products, we used complementary DNA microarrays to analyze gene expression in human umbilical cord blood-derived Mast Cells stimulated via the high-affinity IgE receptor (Fc Epsilon;RI).
One to two hours after Fc Epsilon;RI-dependent stimulation, more than 2,400 genes (about half of which are of unknown function) exhibited 2-200 fold changes in expression.
The transcriptional program included changes in the expression of IL-11 and at least 30 other Cytokines and Chemokines. Human Mast Cells secreted 130-529 pg of IL-11/106 cells by 6 h after stimulation with anti-IgE.
Our initial analysis of the transcriptional program induced in in vitro-derived human Mast Cells stimulated via the Fc Epsilon;RI has identified many products that heretofore have not been associated with this cell type.
But, which may significantly influence Mast Cell function in IgE-associated host responses. We also have demonstrated that Mast Cells stimulated via the Fc Epsilon;RI can secrete IL-11.
Based on the previously reported biological effects of IL-11, our results suggest that production of IL-11 may represent one link between IgE-dependent Mast Cell activation in subjects with allergic Asthma.
And the development of a spectrum of structural changes, in the airways of these individuals; such changes, collectively termed "airway remodeling," can constitute an important long term consequence of Asthma.
InterLeukin-6 And Mast Cells
Conti P, Kempuraj D, Di Gioacchino M, Boucher W, Letourneau R, Kandere K, Barbacane RC, Reale M, Felaco M, Frydas S, Theoharides TC
Allergy Asthma Proc 2002 Sep-Oct;23(5):331-5
University of Chieti School of Medicine, Via dei Vestini, 66100 Chieti, Italy
InterLeukin-6 (IL-6) is a PleioTropic Cytokine (26 kDa) that originally was named Interferon-beta 2 or B-Cell-Stimulating Factor or differentiating B-Cell Factor inducing ImmunoGlobulin production. IL-6 is produced in many diseases.
After secretion, IL-6 binds to its Receptor IL-6R alpha (gp 80), the IL-6R alpha complex then recruits the signal-transducing beta-subunit (gp 130), which is the functional complex for signal transduction.
In addition, activation of Th2 cells or Mast Cells also produce IL-6, which mediates Immune Responses, Inflammation, Acute Phase Responses, Hematopoiesis, Cancer, Inflammatory Bowel Disease, etc. IL-6 also is a crucial Cytokine for Mast Cell maturation.
Human cord blood CD34+ cells differentiate and grow into Mast Cells in the presence of Stem Cell Factor (SCF) and IL-6, causing increases in cell size, frequency of Chymase positive cells, and IntraCellular Histamine levels when compared with cells treated with SCF alone.
Activated Mast Cells increase IL-6 mRNA associated with protein kinase C (PKC) activity. IL-6 also up-regulates Histamine production rather than increases its storage and is an important inducing factor for the expression of ImmunoGlobulin E (IgE) Fc epsilon RI.
The Human Mast Cell: Functions In Physiology And Disease
Krishnaswamy G, Kelley J, Johnson D, Youngberg G, Stone W, Huang SK, Bieber J, Chi DS
Front Biosci 2001 Sep 1;6:D1109-27
East Tennessee State University, The Department of Medicine, Johnson City, Tennessee 37614-1709, USA
Mast Cells are multifunctional, tissue-dwelling cells capable of secreting a wide variety of mediators.
They develop from bone marrow-derived progenitor cells, primed with Stem Cell Factor (SCF), which mediates its actions by interacting with the SCF Receptor or c-kit on the cell surface.
Mast Cells continue their maturation and differentiation in peripheral tissue, developing into two well described subsets of cells, MCT and MCTC Cells, varying in content of Tryptase and Chymase as well as in ImmunoBiology.
Mast Cells are activated by numerous stimuli, including Antigen (acting via the high affinity IgE Receptor, Fc?RI), Superoxides, Complement Proteins, Neuropeptides and Lipoproteins resulting in activation and degranulation.
Following activation, these cells express mediators such as Histamine, Leukotrienes and Prostanoids, as well as Proteases, and many Cytokines and Chemokines, pivotal to the genesis of an inflammatory response.
Recent data suggests that mast cells may play an active role in such diverse diseases as AtheroSclerosis, Malignancy, Asthma, Pulmonary Fibrosis and Arthritis.
Mast cells directly interact with bacteria and appear to play a vital role in host defense against pathogens.
Drugs, such as GlucoCorticoids, Cyclosporine and Cromolyn have been demonstrated to have inhibitory effects on Mast Cell degranulation or mediator release.
The Role Of Th2 Cytokines In Mast Cell Homeostasis
Shelburne CP, Ryan JJ
Immunol Rev 2001 Feb;179:82-93
Virginia Commonwealth University, Department of Biology, Richmond 23284-2012, USA
Homeostatic mechanisms regulating Mast Cell numbers and function in peripheral tissues have largely focused on Cytokines, such as Stem Cell Factor, InterLeukin (IL-3), IL-4, and IL-10, which regulate Mast Cell maintenance and proliferation.
Despite these advances, little attention has been paid to the mechanisms that mediate mature Mast Cell turnover, and control of Mast Cell hyperplasia generated during Th2-mediated responses.
These are important issues, as Mast Cells are now known to be multi-functional Effector Cells, that have the capacity to mediate both Innate and Th2-induced Immune Responses.
Numerous secretagogues may elicit Mast Cells to release a large number of important mediators that can cause chronic inflammation.
Therefore, how Mast Cell Homeostasis is regulated may have significant effects on normal physiology, and contribute to the genesis of inflammatory disease.
Our laboratory has characterized an in vitro model of Mast Cell Homeostasis, by which long-term exposure of murine bone-marrow-derived Mast Cells to the Th2-derived Cytokines IL-3, IL-4, and IL-10, will induce downregulation of critical Mast Cell Effector Proteins such as Kit and Fc Epsilon-RI, followed by Mast Cell Apoptosis.
These data offer a novel role for Th2 Cytokines, acting to both initiate and resolve Mast Cell activation and proliferation. Loss of these signals may contribute to a multitude of diseases, such as MastoCytosis and Allergy.
Mast Cells Are Essential For Early Onset And Severe Disease In A Murine Model Of MS
Secor VH, Secor WE, Gutekunst CA, Brown MA
J Exp Med 2000 Mar 6;191(5):813-822
Emory Univ, School of Medicine, Graduate Program in Immunology and Molecular PathoGenesis, Atlanta, Georgia 30322
In addition to their well characterized role in Allergic Inflammation, recent data confirm that Mast Cells play a more extensive role in a variety of Immune Responses.
However, their contribution to AutoImmune and Neurologic Disease processes has not been investigated.
Experimental Allergic EncephaloMyelitis (EAE) and its human disease counterpart, Multiple Sclerosis, are considered to be CD4+ T-Cell-mediated AutoImmune Diseases affecting the Central Nervous System.
Several lines of indirect evidence suggest that Mast Cells could also play a role in the PathoGenesis of both the human and murine disease.
Using a Myelin Oligodendrocyte Glycoprotein (MOG)-induced model of acute EAE, we show that when compared with their wild-type ConGenic littermates, Mast Cell-deficient W/W(v) mice exhibit significantly:
- Reduced Disease Incidence, Delayed Disease Onset, and Decreased Mean Clinical Scores.
No differences were observed in MOG-specific T-Cell and B-Cell Responses between the two groups, indicating that a global T or B-Cell defect is not present in W/W(v) animals.
Reconstitution of the Mast Cell population in W/W(v) mice restores induction of early and severe disease to wild-type levels, suggesting that Mast Cells are critical for the full manifestation of disease.
These data provide a new mechanism for Immune destruction in EAE and indicate that Mast Cells play a broader role in Neurologic Inflammation.