Expression of Bcl-2 and Bcl-xL in Cutaneous and Bone Marrow Lesions of Mastocytosis

Proc. Natl. Acad. Sci. U.S.A.

Kaieda

Ameri

et al. 2014

Mast cells (MC) are potent innate immune cells that accumulate in chronically inflamed tissues. MC express the IL-33 receptor IL-1 receptor-related protein ST2 at high level, and this IL-1 family cytokine both activates MC directly and primes them to respond to other proinflammatory signals. Whether IL-33 and ST2 play a role in MC survival remains to be defined. In skin-derived human MC, we found that IL-33 attenuated MC apoptosis without altering proliferation, an effect mediated principally through the antiapoptotic molecule B-cell lymphoma-X large (BCLXL). Murine MC demonstrated a similar mechanism, dependent entirely on ST2. In line with these observations, St2−/− mice exhibited reduced numbers of tissue MC in inflamed arthritic joints, in helminthinfected intestine, and in normal peritoneum. Together, these data reveal a cell-intrinsic role for the IL-33/ST2 axis in the regulation of apoptosis in MC, identifying thereby a previously unappreciated pathway supporting expansion of the MC population with inflammation.arthritis | helminth infection M ast cells (MC) are tissue-resident effector cells that contribute both to innate and adaptive immunity (1). MC help defend against bacterial and helminthic infection (2, 3) and play a role in tissue remodeling (4, 5). MC can also contribute to a variety of allergic and nonallergic inflammatory diseases, such as anaphylaxis, atopic dermatitis, asthma, inflammatory arthritis, psoriasis, and multiple sclerosis (6, 7). Under many of these conditions, the number of MC in affected tissues increases by tenfold or more, amplifying the contribution of MC-derived mediators to ongoing inflammation (6-8). Regulation of the MC population is poorly understood, and therapeutic intervention to limit MC accumulation potentially could attenuate injury associated with inflammatory diseases (9, 10).The survival of mature MC in tissues depends on signals from neighboring cells (11,12). The single most important mediator in this process is stem cell factor (SCF), a master regulator of MC proliferation, differentiation, survival, and activation. Mice with genetic mutations affecting SCF or its receptor Kit have few or no MC in healthy or inflamed tissues, whereas activating mutations of Kit give rise to pathologic mastocytosis (13-15). IL-3 is another well-recognized MC growth factor (16). SCF/Kit and IL-3 interface with several antiapoptotic pathways, up-regulating the antiapoptotic protein B-cell lymphoma-2 (BCL-2) and downregulating the proapoptotic protein Bim (14,(17)(18)(19). Aside from SCF/Kit and IL-3, other cytokines have been reported to support MC survival, but their effects appear to be restricted to specific MC subtypes. IL-4 promotes survival of intestinal MC via both BCL-2 and B-cell lymphoma-X large (BCLXL) but may suppress survival in human cord blood MC as well as murine bone marrowderived MC (BMMC) (20-23). IL-10 can either promote or impair survival depending on the type of MC studied (21,22).Recently, substantial attention has focused on the role of IL-33 in MC biolog...

Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 84%

IL-33/ST2 axis promotes mast cell survival via BCLXL

Proc. Natl. Acad. Sci. U.S.A.

Kaieda

Ameri

et al. 2014

“…This is plausible because activation of Kit by stem cell factor or mutation is known to correlate with expression of Bcl-2 in models of hematopoietic stem cells, natural killer cells, mastocytosis, and melanoma. [25][26][27][28][29][30] Conversely, one study found that Bcl-2 expression was associated with wild-type rather than mutant kit gene expression by microarray analysis. 31 The difference between that study and the current study may be related to the number of patients eval-uated or the different analytical approaches, especially because the results of the current study report the expression of Bcl-2 at the protein level rather than at the RNA level, as reported in the microarray study.…”

Section: Discussionmentioning

confidence: 99%

Expression of Bcl‐2 in gastrointestinal stromal tumors

Steinert

Oyarzo

et al. 2006

Cancer

BACKGROUNDThe natural history of gastrointestinal stromal tumor (GIST) has been revolutionized by imatinib mesylate (imatinib) therapy. Before imatinib, Bcl‐2 expression in GIST was associated with a worse prognosis or added no additional prognostic value. To the authors' knowledge, the current study is the first to evaluate Bcl‐2 expression in pre‐imatinib GIST tissue samples as a prognostic marker of progression‐free survival (PFS) time in patients treated with imatinib.METHODSThe cases of 81 patients with GIST who were evaluated between December 15, 2000 and September 1, 2001 were retrospectively reviewed. Clinicopathologic variables were reviewed. GIST cell morphology and patterns of Bcl‐2 expression were described. The methods of Kaplan–Meier and the Cox proportional hazards regression model were used for statistical analysis.RESULTSSixty‐one (75%) patients had tumors that expressed Bcl‐2, and 20 (25%) patients had tumors that were negative for Bcl‐2. All epithelioid tumors (n = 12) expressed Bcl‐2 and tumors with mixed morphology exhibited Bcl‐2 expression in the epithelioid component. A trend toward longer PFS for patients whose tumors expressed Bcl‐2 at a greater immunohistochemical intensity was observed (20.6 mos for no Bcl‐2 expression; 28.3 mos for 1++Bcl‐2 expression; 31.9 mos for 1.5++Bcl‐2 expression; 40.8 mos for 2++Bcl‐2 expresssion; and 35.9 mos for 3++Bcl‐2 expression).CONCLUSIONSIn contrast to studies performed in the preimatinib era, in which Bcl‐2 was found to be a negative prognostic indicator, the current study suggests a trend toward better PFS with increasing Bcl‐2 expression level in GISTs from patients subsequently treated with imatinib. Larger studies may help elucidate the influence of Bcl‐2 expression on PFS after therapy with imatinib. Cancer 2006. © 2006 American Cancer Society.

“…13 In mastocytosis, the expression of Bcl-2 significantly increased while no up-regulation of Bcl-X L was detected. 16 In gastric and colorectal adenocarcinomas, only Bclw was upregulated. 14,15 Besides their selective over-expression in cancer tissues, antiapoptotic Bcl-2 proteins are expressed in healthy tissues in a tissue-selective manner [17][18][19] and function to protect healthy cells.…”

Section: Introductionmentioning

confidence: 99%

Development of selective inhibitors for anti-apoptotic Bcl-2 proteins from BHI-1

Xing

Bioorganic & Medicinal Chemistry

Tang

et al. 2007

A series of inhibitors for anti-apoptotic Bcl-2 proteins based on BHI-1 were synthesized and their binding interactions with Bcl-2, Bcl-X L , and Bcl-w were evaluated. It was found that modification of BHI-1 resulted in varied binding profiles among Bcl-2, Bcl-X L , and Bcl-w and a set of inhibitors with varied selectivity to Bcl-2, Bcl-X L , and Bcl-w protein have been identified. Molecular modeling of the interaction of the BHI-1 based analogs with the anti-apoptotic Bcl-2 proteins suggested that the binding site for the BHI-1 based inhibitor was the least conserved section among Bcl-2, Bcl-X L , and Bcl-w: targeting the non-conserved section may account for the observed selectivity of the BHI-1 based inhibitors among the anti-apoptotic Bcl-2 proteins. The validity of the model was supported by a strong correlation between the model-calculated binding energy and the experimental binding affinity. In summary, our studies suggest that most of the reported inhibitors for antiapoptotic Bcl-2 proteins are nonselective and BHI-1 is a promising template to distinguish among Bcl-2, Bcl-X L , and Bcl-w by targeting the nonconserved domain among the anti-apoptotic Bcl-2 proteins. Molecular-modeling aided rational development of BHI-1 based selective inhibitor for antiapoptotic Bcl-2 proteins is underway.