Major Interests:
Transcriptional regulation of hematopoietic (myeloid)
development and granulocyte (eosinophil) lineage-specific
gene expression. Molecular biology, structural biology
(structure-function relationships) and biologic activities
of eosinophil-derived enzymes (phospholipases, lysophospholipases),
granule cationic proteins/cytotoxins, and galectins
as mediators of eosinophil effector function in allergic
inflammation, tissue damage and disease pathogenesis.
Eosinophil effector functions in inflammation, tissue
remodeling, and fibrosis in asthma, allergy, and other
eosinophil-associated diseases.
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Dr. Stephen J. Ackerman
Professor
PhD, McGill University,
Montreal
Faculty Positions: Harvard
Medical School, Harvard
University, Boston; Mayo
Graduate School of Medicine,
Mayo Clinic and Foundation,
Rochester.
Postdoctoral: Mayo Clinic
and
Foundation, Rochester; Institute
for Cancer Research, Fox
Chase Cancer Center, Philadelphia
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Recent work has included
the cloning, sequencing and characterization of cDNA
and genomic clones encoding eosinophil granule-associated
proteins, isolation of the regulatory regions (promoters
and enhancers) of these eosinophil-specific genes, and
functional characterization of the cis-acting DNA elements
and transcription factors that regulate their expression
during eosinophil development and post-mitotic activation.
We are characterizing the regulatory regions of the
genes encoding the eosinophil-specific alpha (a) subunit
of the IL-5 receptor (IL-5Ra), the eosinophil granule
cationic proteins [major basic protein (MBP) and eosinophil
peroxidase (EPO)], and the Charcot-Leyden crystal (CLC)
protein (Galectin-10). These eosinophil promoters/enhancers
are being analyzed as models for the differential regulation
of myeloid specific genes in general, and eosinophil
specific genes in particular, in the process of the
commitment and differentiation of stem cells and multipotential
bone marrow-derived progenitors to the granulocyte lineages.
Transcription factors thus far shown to regulate eosinophil
development and/or gene expression that are under investigation
include members of the C/EBP family (a , ß, e
and e isoforms), GATA-binding proteins and their co-activators/co-repressors
[Friend of GATA (FOGs)], members of the ets family of
transcriptional regulators including PU.1 and GA-binding
protein (GABP), members of the Egr family, and the RFX
family of transcriptional regulators. We are particularly
interested in the functional interactions of transcriptional
regulators such as the C/EBPs, GATA-binding proteins
(GATA-1 and 2) and PU.1 in terms of their interactions
(antagonism versus synergy) on target genes in the eosinophil
compared to other myeloid lineages, and the enhancer
roles of the RFX and RFX-associated proteins in IL-5
receptor expression. As well, we are characterizing
novel signal transduction pathways mediated via IL-5/IL-5R
signaling in the eosinophil, and the mechanisms that
regulate expression of the soluble versus transmembrane
isoforms of the receptor.
Our work on eosinophil function focuses primarily on
the pro-inflammatory effector roles of eosinophils and
their unique granule cationic proteins and lipolytic
enzymes in the pathogenesis of asthma, allergic and
other eosinophil-associated diseases and hypereosinophilic
syndromes. Research on the cytotoxic and inflammatory
effector functions of eosinophils includes the expression
of recombinant eosinophil proteins (CLC/galectin-10,
proMBP and MBP, eosinophil lysophospholipases) and analyses
of structure-function relationships for their unique
enzymatic and non-enzymatic activities using site-directed
mutagenesis and molecular modeling based on crystallographic
3D structure. Additional projects include investigations
of the mechanisms for eosinophil activation and secretion
of these mediators in response to eosinophil-active
cytokines and other physiologic stimuli. Related projects
characterizing eosinophil effector mechanisms in the
pathophysiology of asthma and other allergic diseases
include studies of the mechanisms by which eosinophils
induce airways dysfunction, fibroblast and epithelial
cell activation, and the production of inflammatory
cytokines and other mediators of tissue remodeling and
pathological tissue fibrosis in the lung, gastrointestinal
tract and other tissues. In this regard, we have recently
developed a model of eosinophil-fibroblast interactions
in which eosinophil products, including TGFß1
and other soluble mediators, induce fibroblast activation
and secretion of fibrogenic cytokines such as IL-6,
and the upregulation of genes involved in extracellular
matrix homeostasis.
Selected Publications:
Yamaguchi Y, Nishio H, Kasahara T, Ackerman SJ, Koyanagi
H and Suda T. Models of lineage switching in hematopoietic
development: a new myeloid-committed eosinophil cell
line (YJ) demonstrates trilineage potential. Leukemia
1998; 12:1430-1439.
Yamaguchi Y, Ackerman SJ, Minegishi N, Yamamoto M and
Suda T. Mechanisms of transcription in the eosinophil:
GATA-1, but not GATA-2 transactivates the P2 promoter
of the granule major basic protein gene. Blood 1998;
91:3447-3458.
Yamaguchi Y, Nishio H, Kishi K, Ackerman SJ and Suda
T. C/EBPß and GATA-1 synergistically regulate
activity of the eosinophil granule major basic protein
promoter: implications for C/EBPß activity in
eosinophil gene expression. Blood 1999; 94:1429-1439.
Swaminathan GJ, Leonidas DD, Savage MP, Ackerman SJ
and Acharya KR. Selective recognition of mannose by
human eosinophil Charcot-Leyden crystal protein (Galectin-10):
A crystallographic study at 1.8Å resolution. Biochemistry
1999; 38:13837-13843.
Furuta GT, Ackerman SJ, Spiess AM, Varga J, Wang MY
and Wershil BK. Eosinophil granule major basic protein
induces IL-8 expression in human intestinal myofibroblasts.
Clin. Exp. Immunol. 2000; 122:35-40.
Du J, Alsayed Y, Xin F, Platanias LC and Ackerman SJ.
Engagement of the CrkL adapter in interleukin-5 signaling
in eosinophils. J. Biol. Chem. 2000; 275:33167-33175.
Paul CC, Aly E-S, Lehman JA, Page SM, Gomez-Cambronero
J, Ackerman SJ, Baumann MA. A human cell line that differentiates
to all myeloid lineages and expresses neutrophil secondary
granule genes. Exp. Hematol. 2000; 28:1373-1380.
Mathur SK, Espenshade BM, Varga J and Ackerman SJ.
Eosinophil-Fibroblast interactions in fibrogenesis:
Eosinophils induce lung fibroblast secretion of IL-6
and expression of genes Involved in extracellular matrix
homeostasis. Chest 2001; 120(1):20.
Ackerman SJ, Liu L,, Kwatia MA, Savage MP, Leonidas
DD, Swaminathan G-J and Acharya KR. Charcot-Leyden crystal
protein (Galectin-10) is not a dual-function galectin
with lysophospholipase activity, but binds a lysophospholipase
inhibitor in a novel structural fashion. J. Biol. Chem.
2002;277:14859-14868.
Du J, Stankiewicz MJ, Liu Y, Xi Q, Schmitz JE and Ackerman
SJ. Novel combinatorial interactions of GATA-1, PU.1
and C/EBPe isoforms regulate transcription of the gene
encoding eosinophil granule major basic protein J. Biol.
Chem. 2002; 277:43481-43394.
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