The anti-tumor action of many chemotherapeutic agents has recently been attributed to the induction of apoptosis in the malignant cell population. In this study, we investigated the ability of extracorporeal photopheresis (ExP) and in vitro PUVA (8-methoxy-psoralen + ultraviolet A) therapy to induce apoptosis in peripheral blood mononuclear cells from Sezary syndrome patients and normal controls. Flow cytometric analysis of ExP- or PUVA-treated peripheral blood lymphocytes demonstrated two distinct cell populations within 24 h of treatment. One population was similar to untreated controls with the other exhibiting characteristics of apoptotic cell death, i.e., a loss of cell volume and an accompanying increase in cell density. This latter population was comprised of cells with DNA strand breaks as determined by the Tdt-mediated deoxyuridine triphosphate-biotin nick end labeling assay. Apoptosis was also confirmed morphologically by fluorescent and electron microscopy as well as by demonstration of characteristic DNA strand breaks (laddering) using gel electrophoresis. Apoptosis was not observed with 8-methoxypsoralen (< or = 300 ng per ml) alone; however, ultraviolet A alone at doses > or = 2 J per cm2 induced apoptosis in lymphocytes. Peripheral blood T-cell subpopulations of Sezary syndrome patients, including the malignant clone, were equally susceptible to apoptosis subsequent to either photopheresis or PUVA treatment. In contrast, monocytes (CD14+/CD45+) appear to be resistant to apoptosis induction by ExP or PUVA treatment. Moreover, ExP-treated and untreated monocytes phagocytized apoptotic, but not untreated, peripheral blood mononuclear cells. ExP and PUVA have been shown to be efficacious and well-tolerated therapies in the treatment of dermatologic diseases and transplant rejection. These data suggest that induction of apoptosis may be an important event for therapeutic efficacy.
Although many cytokines have been implicated in the development and persistence of inflammatory immune responses, it is unknown if any of these are important in inflammatory acne. This study investigated the production of the proinflammatory cytokines interleukin-8 (IL-8), IL-1, and tumor necrosis factor alpha (TNF-␣) by human monocytic cell lines, ThP-1 and U937, and by freshly isolated peripheral blood mononuclear cells from acne patients. Both Propionibacterium acnes and supernatants obtained from 72-h P. acnes cultures could induce significant concentrations of IL-1, TNF-␣, and IL-8 by both cell lines and by peripheral blood mononuclear cells as determined by enzyme-linked immunosorbent assay. There was no significant difference between acne and non-acne subjects. Endotoxin quantification and addition of polymyxin B to assays indicated no lipopolysaccharide (LPS) contamination. P. acnes supernatant was fractionated into components with molecular weights of <3,000, <10,000, and <30,000 and assayed for the ability to induce IL-8 and TNF production in ThP-1 cells. Nearly 90% of the original activity was found in the <30,000-molecular-weight fraction, 50% was in the <10,000-molecular-weight fraction, and only 15% remained in the <3,000-molecularweight fraction. The effluent from the <3,000-molecular-weight fraction contained about 70% activity, indicating that the inducing factor was not retained in the membrane. Incubation of P. acnes supernatant with various concentrations of mutanolysin or lysozyme resulted in a loss of 60% of the original activity. The addition of jimson lectin, which binds peptidoglycan, resulted in a loss of 70% of the activity in a dose-response manner, whereas peanut lectin had little or no effect on the activity. Heating of the P. acnes supernatant to 65 C also had no effect on the activity. Blocking of CD14, a receptor for both LPS and peptidoglycan, reduced cytokine production by >50%, suggesting that the soluble stimulating factor may be a secreted form of peptidoglycan-polysaccharide.
The characterization of the source of the odor in the human axillary region is not only of commercial interest but is also important biologically because axillary extracts can alter the length and timing of the female menstrual cycle. In males, the most abundant odor component is known to be E-3-methyl-2-hexenoic acid (E-3M2H), which is liberated from nonodorous apocrine secretions by axillary microorganisms. Recently, it was found that in the apocrine gland secretions, 3M2H is carried to the skin surface bound to two proteins, apocrine secretion odor-binding proteins 1 and 2 (ASOBI and ASOB2) with apparent molecular masses of 45 kDa and 26 kDa, respectively. To better understand the formation of axillary odors and the structural relationship between 3M2H and its carrier protein, the amino acid sequence and glycosylation pattern of ASOB2 were determined by mass spectrometry. Axillary secretions and odors are derived from an area of the body with exceptional odor-producing capabilities. Several types of skin glands, including apocrine, eccrine, sebaceous, and apoeccrine glands, contribute moisture and substrate to a large permanent population of cutaneous microflora (9). These consist of lipophilic and large colony diptheroids as well as micrococci. These microorganisms generate a variety of odoriferous compounds that characterize the axillary region. In vivo correlations of odor quality and axillary bacterial populations have demonstrated that the aerobic diptheroids are associated with the stronger, more distinct axillary odor (9).A number of investigations of axillary constituents have focused upon the interesting steroidal molecules found there (10, 11). Volatile odoriferous steroids such as 5a-androst-16-en-313-ol (androstenol) and 5a-androst-16-en-3-one (androstenone) as well as nonvolatile steroid sulfates were identified and quantitated by radioimmunoassay and gas chromatography/mass spectrometry (GC/MS) (10,11), The urine/muskylike odors of androstenone and androstenol were thought by some investigators to be suggestive of axillary odor (9-11). However, recent studies (12, 13) have presented both organoleptic and analytical evidence that a mixture of C6-C11, straight-chain, branched, and unsaturated acids constitute the characteristic axillary odor. In combined male samples, the E-isomer of 3-methyl-2-hexenoic acid (3M2H) is the dominant analytical component of the mixture, while in combined female samples the straight-chain acids are present in greater relative abundance (14). The Z-isomer is also present in both genders, however in different relative abundance: 10:1 (E/Z) in males (12) and 16:1 (E/Z) in females (14).More than 30 years ago, it was demonstrated that the odorless precursors of axillary odor are present in apocrine gland secretions and that the characteristic odor arises from interaction of the odorless apocrine secretion precursors with the axillary microflora (15). The water-soluble components of apocrine secretion were found to contain the odorless precursors of the characterist...
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