Biomedical Engineering Reference
In-Depth Information
in morphiceptin activity, administered into the intestinal lumen, compared to
DP4
1/1
, rats thus providing evidence for a role for DP4 as the major enzyme
responsible for morphiceptin degradation
174
and further supporting a role for
DP4 in the management of analgesia. b-Casomorphin is a milk-derived peptide
with opioid activity with the ability to pass through the gut barrier and function
on the immunological as well as neurological systems.
175
Proteolytic degrada-
tion of b-casomorphin by DP4 has been detected in a number of studies
including a recent report by Iwan et al., who demonstrated the transportation
of b-casomorphin across Caco-2, a human intestinal cell line, monolayers
known to express high levels of DP4.
175
More recently, DP4 has been shown to
cleave an additional endogenous opioid peptide, hemorphin-7, that is derived
from proteolytic degradation of hemoglobin.
181
Thus, there is substantial evi-
dence supporting roles for DP4 in the modulation of analgesia via its proteo-
lytic activity.
1.6.4 Immune System and Disorders
Chemokines are a large family of small secretory proteins (5 to 10 kDa)
involved in the immune system and in numerous inflammatory-related dis-
orders including leukocyte maturation, migration, and chemoattractant activ-
ities. Chemokines interact with their cell-surface receptors via their N-terminal
region, and so potential modulation of their receptor selectivity and regulation
of their activity via proteolytic cleavage is of interest. DP4 cleavage of che-
mokines has been readily demonstrated, and kinetics indicate they could be
physiological substrates of DP4.
155
N-terminal truncation by DP4 can result in
a shift in receptor specificity and alter or abolish the chemoattractant activity of
RANTES, SDF1-a/b, MDC, eotaxin, IP-10, I-TAC, and Mig towards lym-
phocytes, monocytes, CD34(
รพ
) progenitor cells, and eosinophils, and may
reduce any anti-HIV-1 activities of these chemokines.
182,183,186,189,190,224,225
Increased chemotactic activity may also result, as occurs for LD78b
(3-70)
after
its derivation from LD78a
(1-70)
by DP4.
191
LD78b
(3-70)
displays enhanced
chemotactic activity towards monocytes and maintains strong anti-HIV-1
activity. Both IP-10 and Mig can inhibit the angiogenic process, a feature that is
retained following their truncation by DP4.
225
Some of the altered migratory
capabilities of DP4 expressing tumor cells may be associated with its chemokine
substrates. In conjunction with the activity of aminopeptidase N, the involve-
ment of DP4 in I-TAC proteolysis results in impaired migration of micro-
vascular endothelial cells (HMVEC),
226
while DP4 degradation of SDF-1 is
suggested to be involved in the metastasis of prostate cancer cell lines.
227
Sezary
syndrome is a rare form of T-cell lymphoma affecting the skin in which a
characteristic loss of DP4 from the cell surface of T lymphocytes occurs. This
loss of DP4 is maintained upon T lymphocyte infiltration of the skin. Narducci
et al. found that Sezary syndrome T-cells express the functionally active SDF-1
receptor, CXCR4, and that skin cells of patients produce a large amount of the
SDF-1 ligand, thus making it likely that in the absence of DP4 expression,
