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apoptosis, positive induction 76 arachidonic acid (AA) and leukotrienes
large group of anti-apoptosis members that, when overexpressed,
prevent apoptosis and a large group of pro-apoptosis
members that, when overexpressed, induce apoptosis. The
balance between the anti-apoptotic and pro-apoptotic Bcl-2
family members may be critical in determining whether a
cell undergoes apoptosis. Thus, the suppressor activity of
the anti-apoptotic Bcl-2 family appears to be negated by the
pro-apoptotic members. Many members of the pro-apoptotic
Bcl-2 family are present in cells at levels sufficient to induce
apoptosis; however, these members do not induce apoptosis
because their activity is maintained in a latent form. Bax
is present in the cytosols of live cells. After an appropriate
signal, Bax undergoes a conformational change and moves
to the mitochondrial membranes, where it causes release of
mitochondrial cytochrome c into the cytosols. BID is also
present in the cytosols of live cells. After cleavage by caspase
8, it moves to the mitochondria, where it causes release of
cytochrome c, possibly by altering the conformation of Bax.
Similarly, BAK appears to undergo a conformational change
that converts it from an inactive to an active state. Thus,
understanding the molecular mechanisms responsible for
regulating the Bcl-2 family activities creates the potential
for pharmaceutical intervention to control apoptosis. The
viability of many cells is dependent on a constant or intermittent
supply of cytokines or growth factors. In the absence
of an apoptosis-suppressing cytokine, cells may undergo
apoptosis. Bad is a pro-apoptotic member of the Bcl-2 family
and is sequestered in the cytosol when cytokines are
present. Cytokine binding can activate PI3 kinase, which
phosphorylates Akt/PKB, which in turn phosphorylates
Bad. Phosphorylated Bad is sequestered in the cytosol by
the 14-3-3 protein. Removal of the cytokine turns the kinase
pathway off, the phosphorylation state of Bad shifts to the
dephosphorylated form, and dephosphorylated Bad causes
release of cytochrome c from the mitochondria.
apoptosis, positive induction
Two central pathways lead to apoptosis: (1) positive induction
by ligand binding to plasma membrane receptor, and (2)
negative induction by loss of suppressor activity. Each pathway
leads to activation of cysteine proteases with homology to
IL-1β-converting enzyme (ICE) (i.e., caspases). Positive
induction involves ligands related to tumor necrosis factor
(TNF). Ligands are typically trimeric and bind to cell surface
receptors, causing aggregation (trimerization) of the receptors.
Receptor oligomerization orients their cytosolic death domains
into a configuration that recruits adaptor proteins. The adaptor
complex recruits caspase 8. Caspase 8 is activated, and the
cascade of caspase-mediated disassembly proceeds.
apoptosis, suppressors
The induction of apoptosis or progression through the process
of apoptosis is inhibited by a group of proteins known as
inhibitors of apoptosis (IAPs). These proteins contain baculovirus
IAP repeat (BIR) domains near their amino termini.
The BIR domain can bind some caspases. Many members
of the IAP family of proteins block proteolytic activation of
caspase 3 and 7. XIAP, cIAP-1, and cIAP-2 appear to block
cytochrome-c-induced activation of caspase 9, thereby preventing
initiation of the caspase cascade. Because cIAP-1 and
cIAP-2 were first identified as components in the cytosolic
death domain-induced complex associated with the tumor
necrosis factor (TNF) family of receptors, they may inhibit
apoptosis by additional mechanisms.
appendix, vermiform
A gut-associated secondary lymphoid tissue situated at the
ileocecal junction of the gastrointestinal tract.
APR (acute phase response)
A nonspecific response by an individual stimulated by interleukin-1,
interleukin-6, tumor necrosis factor, and interferons.
C-reactive protein may show a striking rise within a
few hours. Infection, inflammation, tissue injury, and very
infrequently neoplasm may be associated with APR. The
liver produces acute phase proteins at an accelerated rate,
and the endocrine system is affected with elevated gluconeogenesis,
impaired thyroid function, and other changes.
Immunologic and hematopoietic system changes include
hypergammaglobulinemia and leukocytosis with a shift to
left. Diminished formation of albumin, elevated ceruloplasmin,
and diminished zinc and iron are observed.
APT (alum-precipitated toxoid)
Refer to alum-precipitated antigen.
Aquaphor ®
An emulsifying preparation of lanolin used extensively in
the past to prepare the water-in-oil emulsion immunologic
adjuvants of the Freund type.
aqueous adjuvants
Freund’s adjuvants are not used in humans because of the
ease with which hypersensitivity is induced and the unpredictability
of local reactions. A number of water-soluble synthetic
components comprising active moieties of mycobacterial
cell walls have been synthesized in search of more adequate
adjuvants. One of them is muramyl dipeptide (MDP), which is
active when administered by the oral route. MDP in water is
extremely active as an adjuvant and is not generally toxic when
administered at high doses. It is not mitogenic, immunogenic,
or antigenic and is rapidly eliminated from the animal body.
The simplicity of its chemical structure allows the study of
the targets of its action in the immune system. Other synthetic
adjuvant compounds are polynucleotides such as poly-inosinepoly-cytidine
(poly I:C), the structure of which is similar to
those of native nucleotides. The mechanism of action involves
signals that are rapidly received by the immune system, as
such compounds are destroyed in 5 to 10 minutes by the
nucleases of the serum. The prevalent concept is that adjuvants
have a number of other regulatory activities on the immune
response, and the term adjuvant may be replaced by immunoregulatory
molecule.
arachidonic acid (AA) and leukotrienes
Critical constituents of mammalian cell membranes. AA is
released from membrane phospholipids as a consequence of
membrane alterations or receptor-mediated signaling that leads
to activation of phospholipase A 2 (PLA 2). Oxidative metabolism
of AA through cyclooxygenase leads to the formation of
various prostaglandins through the cytochrome P-450 system
or through one of the lipoxygenases. Molecules derived from
the lipoxygenase pathway of arachidonic acid are termed leukotrienes
(LTs). They are derived from the combined actions
of 5-lipoxygenase (5-LOX) and 5-LOX-activating protein
(FLAP). Initially 5-hydroperoxyeicosatetraenoic (5-HPETE)
acid is formed followed by LTA 4. LTB 4 is an enzymatic,
hydrolytic product of LTA 4. It differs from the LTC 4, LTD 4,
and LTE 4 leukotrienes in that it does not have a peptide
component. LTB 4 has powerful leukocytotropic effects. It
is a powerful chemokinetic and chemotactic agent with the
ability to induce neutrophil aggregation, degranulation, hexose