Institutionen för medicin / Department of Medicine
Abstract
Gene-encoded antimicrobial peptides serve a protective role in host
defense. They are multifunctional effector molecules in innate immunity -
the nonadaptive immune system -with the capacity to kill a broad spectrum
of microorganisms. In contrast to adaptive immunity, which is highly
specific, the innate immune system provides a rapid and nonspecific
response, thereby contributing to the first line of defense.
Cathelecidins constitute a family of antibacterial peptides. hCAP1 8, the
precursor of the LL-37 antimicrobial peptide, is the only cathelecidin in
humans while there are several in other species.
We first analyzed fluid from wounds with different etiology for
antibacterial and biochemical factors. We showed that wound fluid can be
analyzed reproducibly and characterized biochemically. Separation and
identification of such fluids yielded peptide components likely to
reflect necrosis and to function as antibacterial and possible wound
healing factors (Paper 1).
We studied the role of hCAP1 8 in normal wound healing and in chronic
non-healing ulcers. Using skin biopsies from healthy volunteers and from
patients, we determined the level and expression pattern of hCAP1 8. Our
results demonstrate the presence of hCAP1 8 in both types of wounds.
Maximal levels of hCAP 18 were attained at 12h-2days post-wounding in
surgical wounds. Total hCAP 18 protein levels in the chronic ulcers were
below 20% of the maxima detected in the surgical wounds. Processed active
LL-37 peptide was demonstrated in normal wound healing but was barely
detectable in the chronic ulcers (Paper 2).
In addition to providing a mechanical barrier between the body and the
environment epithelia function as an immunological organ. Investigating
the expression of hCAP 18 in inflammatory skin disorders we found up-
regulation of the hCAP 18 gene in the keratinocytes of inflammatory
dermatoses such as lesional psoriasis, nickel allergy and atopic
dermatitis, but not in normal quiescent epidermis (Paper3).
Further investigation of hCAP1 8 in squamous epithelia demonstrated that
hCAP1 8 was constantly expressed at both RNA and protein levels in
epithelia of tongue, esophagus, cervix and vagina. Expression of IL- 6
co-localized with hCAP 18 in these tissues. The hCAP 18 gene contains
promotor elements that are potentially regulated by IL-6, and our
findings suggest a potential local mechanism for the up-regulation of
hCAP 18 on epithelial surfaces (Paper 4).
To assess the potential role of hCAP 18 in tumor host defense, we
investigated its expression in human breast cancer of varying types and
malignancy. hCAP 18 was strongly up-regulated in the tumor cells compared
to the low constitutive expression in normal benign mammary epithelia.
Further, the highest levels of hCAP 18 protein were detected in the most
malignant tumors, and immunoblotting revealed processed active LL-37 only
in these tumors. Thus our results do not support a protective role for
hCAP 18 in tumor host defense, but rather suggest that hCAP 18 may
provide a survival advantage for the tumor (Paper 5).
In summary our studies reveal a role for the innate immunity effector
hCAP 18 in epithelial defense