Paget's disease of the breast: a clinical perspective.

Paget's disease of the breast is a rare disorder of the nipple-areola complex often associated with an underlying in situ or invasive carcinoma. Eczematoid changes of the nipple-areola complex and persistent soreness or itching should raise suspicion of this disease. The histogenesis of Paget's disease of the breast continues to be debated and is important when considering treatment options. The epidermotropic theory suggests that Paget's cells are ductal carcinoma cells that have migrated from an underlying carcinoma of the breast parenchyma to the epidermis of the nipple. The in situ transformation theory has been proposed to explain the development of this disorder in patients in whom an underlying mammary carcinoma is not found or when there is an underlying carcinoma anatomically remote from the nipple-areola complex. Paget's cells are believed to arise as malignant cells in the epidermis of the nipple independent from any other pathologic process within the breast parenchyma. The current standard treatment of biopsy-proven Paget's disease involves mastectomy, although some studies have proposed the use of breast conservation therapy for patients in whom an underlying breast cancer cannot be located. We propose a treatment algorithm for patients presenting with Paget's disease of the breast.

Tumors of the oral cavity and pharynx.

We have compiled all the reported cases of smooth muscle (stromal) tumors of the oral cavity and pharynx from 1884 through 1996. Our collective data included 139 leiomyomas (LM) and 68 leiomyosarcomas (LMS); but because we did not have sufficient information for 13 cases of LM, we report on only 126; and we report on only 66 of 68 cases of LMS. The peak age of incidence was 40 to 49 years for benign tumors and 50 to 59 years for malignant lesions, with the incidence in men slightly predominating over that in women. The most common sites of LM of the oral cavity and pharynx were the lips, tongue, and hard and soft palate. The most common sites of LMS included the maxilla and mandible. More than 40% of LMs presented as an intraoral mass, and more than half were known to be present for longer than 1 year. About 10% presented with pain, difficulty chewing or swallowing, swelling, toothache or loose teeth, or a combination of these symptoms. Patients with LMS were much more likely to have obvious symptoms of shorter duration, and one-third presented with pain or swelling (or both). Other relatively common symptoms of LMS included tenderness, interference with dentures, or an intraoral mass. In this review, there were almost twice as many LMs as LMSs, which was consistent with smooth muscle tumors found in other areas of the gastrointestinal tract.

Tumors of the esophagus.

This collective review includes all available case reports of smooth muscle (stromal) tumors of the esophagus in the world literature. Compiling this review, we endeavored to examine cumulative and recently collected data of both benign and malignant esophageal smooth muscle tumors found in the literature spanning the period from 1875 to 1996, which totaled 1679 leiomyomas (LMs) and 165 leiomyosarcomas (LMSs). The peak age of occurrence of benign smooth muscle tumors in the esophagus was found to be between the ages of 30 and 59, whereas the highest frequency of malignant tumors was seen later in life, during the decade from age 60 to 69. The most common location of both LMs and LMSs was the lower third of the esophagus. Their patterns of growth differed; LMs were more likely to grow intramurally, and LMSs were predominantly intraluminal. Most patients with LMs presented with dysphagia and pain or discomfort; patients with LMSs additionally commonly complained of weight loss. As with smooth muscle tumors of other areas of the gastrointestinal tract, the duration of symptoms averaged 1 month to 1 year, and malignant tumors grew to larger sizes than benign neoplasms. Approximately one-third of LMSs had metastasized at diagnosis, and there was a 5-year survival rate of approximately 20%.

Tumors of the appendix and colon.

This collective review includes all available case reports of smooth muscle (stromal) tumors of the appendix and large intestine in the world literature. When compiling this review, we endeavored to examine cumulative as well as recently collected data on both benign and malignant smooth muscle tumors spanning the period 1875 to 1996. In total, there were reports of 331 leiomyomas (LMs) and 263 leiomyosarcomas (LMSs). The peak age of incidence of LM was 30 to 39 years, and the peak age of incidence of LMSs was 50 to 59 years. The female/male ratio was slightly higher for LM, and the male/female ratio was higher for LMS. The descending colon and sigmoid colon were the most common sites of both benign and malignant smooth muscle tumors. The growth of LMs most often occurred extraluminally, whereas LMSs tended to grow within the lumen of the colon. With both tumor types pain was the most frequent presenting complaint, followed less commonly by complaints of a palpable mass or gastrointestinal bleeding. LMSs tended to be larger at diagnosis than LMs, though the duration of symptoms for both types of tumor was most often reported to be between 1 month and 1 year. Finally, LMSs were found to metastasize mo

Tumors of the stomach.

This collective review includes all available case reports of smooth muscle (stromal) tumors of the stomach in the world literature from 1762 to 1996. It updates our previous review from 1767 to 1959. Overall, we identified 2189 patients with leiomyoma (LM) and 1594 with leiomyosarcoma (LMS). The peak age of incidence of LM was 50 to 59 years, while LMS was most frequently seen between ages 60 and 69. Women were more likely to develop LM, and men more commonly presented with malignant smooth muscle tumors of the stomach. Concerning the patterns of growth, LMs were more likely to grow intraluminally (endogastric), whereas LMSs were predominantly exogastric. The most common site of LMs was on the anterior or posterior wall of the body of the stomach; LMSs were most likely found along the greater curve. The presenting symptoms of both types of smooth muscle tumors were similar; in decreasing order of frequency they were bleeding, pain, palpable mass, and weight loss. Interestingly, there was no correlation between the size of the tumor and signs or symptoms of bleeding, pain, weight loss, or ulceration, although patients with LMSs were more likely to report weight loss than patients with benign tumors. For LMS, there seemed to be no correlation between tumor size or location and rate of metastasis, although the tumors that grew in a dumbbell shape (i.e., both intraluminally and extraluminally) had a higher frequency of metastasis than other growth patterns. Overall, the rate of metastasis at diagnosis was 35.4%, with the liver, spleen, and regional lymph nodes the most common sites.

Tumors of the small intestine.

This collective review includes all available case reports and series of smooth muscle (stromal) tumors of the small intestine in the world literature from 1881 to 1996. We identified 1074 patients with leiomyoma (LM) and 1689 with leiomyosarcoma (LMS). Our purpose was to update our previous review, which encompassed case reports and series from 1881 to 1959, which included 350 LMs and 257 LMSs. The peak incidence of smooth muscle tumors in the small intestine in both male and female patients was between the ages of 50 and 59. Most commonly, the presenting complaint was gastrointestinal bleeding. Computed tomography was found to detect LM and LMS most successfully and had the additional advantage of locating metastatic disease. The jejunum contained the highest numbers of smooth muscle tumors, followed by the ileum and then the duodenum, with malignant lesions in all locations typically attaining larger diameters than benign tumors. The overall rate of metastatic spread of LMS ranged from 24% to 50%, with the liver being most commonly involved. Unlike other sarcomas, both hematogenous and lymphatic spread were common. The 5-year survival of 705 patients with LMS from 22 series was 27. 8%. For both benign and malignant smooth muscle tumors of the small intestine, surgery remains the treatment of choice, with little efficacy reported for irradiation, chemotherapy, or both.

Tumors of the rectum and anal canal.

This collective review includes all available case reports of smooth muscle (stromal) tumors of the rectum and anal canal in the world literature. When compiling this review we endeavored to present cumulative and recently collected data of both benign and malignant smooth muscle tumors found in the literature spanning the period from 1881 to 1996, which totaled 432 leiomyomas (LMs) and 480 leiomyosarcomas (LMSs) of the anus and rectum. The peak age of frequency for LMs was 40 to 59 years and 50 to 69 years for LMSs; men were slightly more likely to develop both benign and malignant anorectal smooth muscle tumors than women. Intraluminal growth of both LMs and LMSs was more frequently seen than extraluminal or intramural patterns, and tumors were more likely to be found in the rectum than in the anus. Patients with LMs presented most commonly with gastrointestinal (GI) bleeding, a palpable mass, or anorectal pain. As with smooth muscle tumors in other areas of the alimentary tract, symptoms likely persisted for less than 1 year prior to diagnosis. As was also the case for these neoplasms in other GI locations, LMSs tended to be larger than LMs. Approximately 20% of LMSs reported from 1881 to 1996 had metastasized at diagnoses. The local recurrence rate for resectable tumors was more than 80%, exceeding the propensity of LMSs in other areas of the GI tract to recur.

Prophylactic surgery for women at high risk for breast cancer.

Women at high risk for the development of breast cancer have several options open to them including increased cancer surveillance, prophylactic mastectomy and/or oophorectomy, and chemoprevention. We consider high-risk women to be those with known BRCA mutations or a strong family history characterized by multiple relatives with breast cancer, early age at diagnosis, and in some families, ovarian cancer. We present existing data regarding prophylactic surgery for these women. Essentially, a woman at high risk for breast cancer may choose to undergo bilateral prophylactic mastectomy, with or without reconstruction. For patients who have a known breast cancer, contralateral mastectomy is also an option. Finally, for women in families with a strong incidence of ovarian cancer, prophylactic oophorectomy can be considered.

Direct killing of interleukin-2-transfected tumor cells by human neutrophils.

We have previously established that human polymorphonuclear cells (PMN) express IL-2R beta- and gamma-chains and that addition of IL-2 maintains the viability of PMN by preventing these cells from undergoing programmed cell death. The purpose of this study was to examine whether IL-2-releasing tumor cells are capable of stimulating PMN tumoricidal activity. We therefore investigated the ability of PMN to kill IL-2-transfected tumor cells using normal human PMN directed against the murine mammary adenocarcinoma TS/A engineered to release high amounts of murine IL-2 (3,600 U, B6) compared with TS/A parental cells and TS/A tumor cells transfected with the neomycin-resistance (NEO) gene only. The potency of PMN as IL-2-induced killer cells was indicated by the low number of cells required for killing (effector cell:target cell ratio 10:1) and the degree of tumor cell lysis (68+/-10%). Evidence for the role of IL-2 as a mediator of tumor cytotoxicity by PMN was substantiated by inhibition of tumor killing with anti-IL-2 and anti-IL-2R beta monoclonal antibodies (MAbs). Furthermore, in vivo depletion of mature granulocytes using MAb RB6-8C5 resulted in B6 adenocarcinoma growth, thereby confirming a direct role for IL-2-activated PMN in tumor cytolysis. Lastly, we suggest that one possible mechanism involved in IL-2-induced PMN cytotoxicity against the B6 clone occurs via the nitric oxide pathway, which could be inhibited upon addition of the arginine analog, N(G)-monomethyl-L-arginine.

Interleukin-12 synergizes with interleukin-2 to generate lymphokine-activated killer activity in peripheral blood mononuclear cells cultured in ovarian cancer ascitic fluid.

OBJECTIVES: The ascites-associated lymphocytes in ovarian cancer have altered immunologic function, and cell-free ascitic fluid has immunomodulating properties. We determined (1) whether interleukin (IL)-2 could induce lymphokine-activated killer (LAK) activity in normal peripheral blood mononuclear cells (PBMC) cultured in ovarian cancer ascitic fluid, and (2) whether IL-12 could synergize with IL-2 to generate LAK activity in normal PBMC cultured in ascitic fluid. METHODS: Normal PBMC were cultured in control medium and in media consisting of 50% ascitic fluid (ascitic medium), with and without IL-2 and IL-12. Cell activation to assess LAK activity (cell lysis) was determined in a 51Cr-release assay with the tumor cell lines FMEX and SKOV3 as target cells. To determine a possible mechanism for any synergistic effect, the expression of perforin, a pore-forming protein, was determined by Northern blot analysis. RESULTS: Interleukin-2 alone could not induce LAK activity in normal PBMC cultured in 50% ascitic fluid for up to 3 days. Interleukin-12 did mediate some or minimal LAK activity after 1, 2, or 3 days of incubation in control medium or in 50% ascitic fluid. When IL-2 and IL-12 were used in combination, PBMC cultured for 3 days in 50% ascitic fluid had remarkably high lytic activity against FMEX and SKOV3 tumor cells. In some experiments, this cytotoxicity was greater than that in PBMC cultured in control medium with IL-2 and IL-12. Lower concentrations of IL-12 (1 U/mL) with IL-2 (100 U/mL) were as effective as, and often more effective than, higher doses of IL-12 with IL-2. Very low-dose IL-12 (0.01-0.03 U/mL) in combination with IL-2 also induced a range of cytotoxicities. Only the combination of IL-2 and IL-12 up-regulated expression of perforin mRNA in ascitic medium. CONCLUSIONS: The cytotoxicity responses of PBMC cultured in ascitic fluid in the presence of IL-2 and IL-12 are complex. Low-dose IL-2 and IL-12 can overcome the inhibitory property of ascitic fluid on LAK generation and can restore and enhance cytotoxic activity, possibly by reconstituting the expression of perforin. These findings may have therapeutic potential.

Role of extracellular adenosine triphosphate in the cytotoxic T-lymphocyte-mediated lysis of antigen presenting cells.

The lysis of antigen presenting cells (APCs) by cytotoxic T lymphocytes (CTLs) may be one mechanism whereby an immune response is downregulated by Staphylococcus superantigens. Disappearance of monocytes/macrophages from staphylococcal enterotoxin A (SEA)-activated peripheral blood mononuclear cell (PBMC) cultures, but not from control PBMC cultures was seen by flow cytometry. Recently, adenosine triphosphate (ATP) has been described as an effector molecule in CTL-mediated lysis of some murine tumor target cells. We have also shown that ATP caused the lysis of human macrophages, and that treatment of cells with interferon gamma (IFN gamma) rendered macrophages significantly more sensitive to ATP than untreated cells. To show that this purine nucleotide may play a role in modulating the immune system, we generated human CTLs that were stimulated with SEA, and used them as effector cells against SEA-pulsed autologous macrophages. CTLs were found to specifically lyse SEA-pulsed macrophages, while control, unpulsed, macrophages were unaffected. The addition of hexokinase, an enzyme that hydrolyzes ATP, significantly abrogated the killing of SEA-pulsed cells during the assay. In examining the mechanism of cytotoxicity, electron microscopy showed that macrophages incubated with both ATP and CTLs underwent necrosis, rather than apoptosis. From these results, it is suggested that ATP is released from CTLs during antigen presentation, and that IFN gamma-activated macrophages, which are inherently more sensitive to this mediator, are readily lysed and therefore removed from circulation, thus downregulating an immune response.

Interleukin-12-mediated tumoricidal activity of patient lymphocytes in an autologous in vitro ovarian cancer assay system.

This study was designed to examine if interleukin-12 (IL-12) can induce cytolytic function of lymphocytes from ovarian cancer patients against either an ovarian cancer cell line or their own autologous tumor cells. Lymphocytes were obtained from the peripheral blood or ascites of ovarian cancer patients and activated with IL-12 alone or concomitantly with interleukin 2 (IL-2) for 2 to 3 days. Activation of lymphocytes and assessment of tumoricidal function by a chromium release assay were performed directly in a standard control medium (RPMI 1640 containing 2 mM glutamine, 100 micrograms/ml streptomycin, 100 units penicillin, 5% heat-inactivated human AB serum, and 5 mM 4-(2-hydroxyethyl)-1-piperazinesulfonic acid) and in 50% ascitic fluid (50% by volume filter-sterilized ascites with 50% of the above-mentioned control medium). Target cells were added directly into the medium in which the lymphocytes were activated in order to more closely mimic in vivo conditions. Lymphocytes, activated by IL-12 in 50% ascitic fluid, were able to lyse autologous tumor cells in 3 of 6 assays and were able to lyse SKOV3 cells (an ovarian cancer cell line) in 5 of 7 assays. The results were not significantly different in the control medium. When both IL-2 and IL-12 were used to activate lymphocytes in 50% ascitic fluid, significant cytotoxicity was generated in 6 of 6 autologous assays and in all 7 patient assays using SKOV3 as a target (P < 0.05). Synergy between the two cytokines was seen in all 13 patient assays in ascitic medium compared to only 5 of 13 assays in control medium. Additionally, when lymphocytes were stimulated with both IL-2 and IL-12, significantly greater cytotoxicity was seen in the ascitic fluid medium compared to the control medium in 13 of 14 assays (P < 0.05). No significant tumoricidal activity was seen by lymphocytes maintained in either medium without the addition of IL-2 or IL-12. Ascitic fluid consistently potentiates the synergy between IL-2 and IL-12 in generating cytotoxicity against ovarian cancer cells but does not increase cytotoxicity induced by IL-12 alone. IL-12 by itself activates tumoricidal activity of lymphocytes in ascitic fluid; however, the addition of IL-2 increases the degree and consistency of this effect. These data support the possibility that IL-12 may warrant further investigation as a potential therapeutic agent in the treatment of advanced ovarian cancer.

Inhibition of extracellular ATP-mediated lysis of human macrophages by calmodulin antagonists.

Lysis of human culture-derived macrophages by extracellular ATP has recently been described, and treatment of macrophages with interferon-gamma rendered those cells significantly more sensitive to lysis. In addition, cell death occurred more rapidly in interferon (IFN)-treated cells than in untreated macrophages. In an attempt to identify the mechanism by which extracellular ATP affects macrophages, as well as to explore the differences between interferon-gamma-treated and untreated macrophages, selected metabolic inhibitors were included in the lytic assays. Of the compounds tested, three antagonists of calmodulin-linked pathways (trifluoperazine, KN-62, and calmidazolium) blocked the ATP-mediated lysis of both interferon-gamma-treated and colony-stimulating factor-treated macrophages in a dose-dependent manner. Early signals of the ATP ligation of the P2Z purinoceptors of human macrophages included increases in cytosolic [Ca2+] and depolarization of the plasma membrane. However, the inclusion of calmodulin antagonists in these assays did not abrogate either effect. These results suggest that the mechanism which mediates the efflux of 51Cr-labeled proteins from ATP-lysed macrophages is distinct from calcium mobilization and membrane depolarization, and may involve the generation of secondary pores/channels in the plasma membrane via a calmodulin-linked pathway.

Restoration of lytic function in a human natural killer cell line by gene transfection.

NK cells can recognize and lyse target cells without restriction by the MHC. The molecular interaction responsible for NK cell recognition is poorly understood. It has been frequently suggested that the loss of beta 2 integrin in immune competent cells may lead to dysfunction due to inadequate cell-cell interaction. We examined the role of lymphocyte functional adhesion molecule-1 in the function of a human natural killer leukemia cell line, YT-1. A mutant YT-1(-) cell subclone showed an absence of killing activity against a B lymphoma cell line, compared with that against a CD11a/CD18 positive parental cell line, YT-1(+) cells. We found that this loss of cytotoxicity was correlated with lack of surface expression of CD11a/CD18 molecules due to the mutation of the CD18 gene. Using gene transfer experiments, we provide strong evidence demonstrating that CD18 transfection to this mutant NK cell line, YT-1(-), restored the surface expression of CD11a/CD18, and this restoration was accompanied by reexpression of cytotoxic function.

IL-8 production by peripheral blood mononuclear cells in nephrotic patients.

We studied the interleukin 8 (IL-8) gene expression by peripheral blood mononuclear cells (PBMC) and the IL-8 serum concentration in patients with idiopathic minimal lesion nephrotic syndrome (IMLNS) and other glomerulopathies. PBMC from eight of the nine (IMLNS) patients in relapse demonstrated the presence of IL-8 mRNA. All three IMLNS patients in remission (P = 0.0026 when compared to patients in relapse) and the two patients with nephrotic syndrome with other glomerulopathies failed to elicit an IL-8 mRNA response. Eleven of the 12 IMLNS patients in relapse showed IL-8 serum concentration above the level of detection. Only one of the seven patients in remission had detectable serum levels of IL-8 (P = 0.0033 when compared to levels from IMLNS patients in relapse). IL-8 serum levels were not detectable in three patients with nephrotic syndrome and other glomerulopathies. Supernatants of PBMC cultures from IMLNS patients in relapse increased the 35sulfate uptake by rat GBM. This effect was abolished by the addition of anti-IL-8 neutralizing antibody to the culture media and reproduced by the addition to the media of IL-8 in concentrations found in the serum of IMLNS patients in relapse. Finally, the effect of IL-8 on the 35sulfate turnover of the glomerular basement membrane (GBM) sulfated compounds was evaluated in vitro. A significant decrease in the percentage of residual 35sulfate incorporated in the GBM (41 +/- 5, mean +/- SEM) was observed in cultures treated with IL-8 as compared to those that were not treated with IL-8 (58 +/- 8, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Expression of interleukin-2 receptor alpha (IL-2R alpha) mRNA and protein in advanced epithelial ovarian cancer.

Advanced epithelial ovarian cancer has recently been identified by us to be associated with elevated serum and ascitic levels of the soluble Interleukin-2 receptor alpha (sIL-2R alpha). To determine the cellular source of sIL-2R alpha, the expression of IL-2R alpha was assessed at the mRNA and protein level in peripheral blood mononuclear cells (PBMC), in ovarian cancer ascitic cell infiltrates and in primary and metastatic epithelial ovarian cancer lesions by immunochemistry, by flow cytometric analysis and by in situ hybridization (ISH). Normal PBMC and the PBMC from ovarian cancer patients had a low or undetectable level of IL-2R alpha mRNA and of IL-2R alpha cell-surface protein expression. Flow cytometric analysis of the heterogeneous ascitic infiltrates revealed few cells positively expressing cell-surface IL-2R alpha. By immunocytochemistry, 1-2% of leukocytes in the ascitic infiltrates were IL-2R alpha+. Cytologically these IL-2R alpha+ cells were lymphocytes. Frozen sections of primary and metastatic ovarian cancer lesions showed sparse lymphocytic infiltration and very small numbers of these tumour infiltrating lymphocytes (TIL) were IL-2R alpha+. In situ hybridization demonstrated that although less than 2% of leukocytes in the ascitic infiltrate had detectable levels of IL-2R alpha mRNA, there was a wide range in the level of mRNA expression in these positive cells. The cells expressing IL-2R alpha mRNA had the cytologic characteristics of lymphocytes. Similarly, in the frozen sections of the solid tumours, there was a range in the level of IL-2R alpha mRNA expression in the few TIL that expressed IL-2R alpha. Importantly, ovarian cancer cells and mesothelial cells did not express IL-2R alpha mRNA or IL-2R alpha protein. Our observations lead us to conclude that lymphocytes are the main, if not the only, source of sIL-2R alpha in ovarian cancer patients. Although cells expressing IL-2R alpha were relatively few in number, as the source of the high levels of sIL-2R alpha, they may contribute to the immunosuppression of ascitic lymphocytes in advanced epithelial ovarian cancer.

Induction of IL-8 gene expression in human polymorphonuclear neutrophils by recombinant IL-2.

Induction of IL-8 gene expression was investigated in IL-2-stimulated circulating peripheral blood polymorphonuclear neutrophils (PMN). Brief exposure of normal PMN to human rIL-2 enhanced both transcriptional and translational expression of IL-8. The IL-8 mRNA was first detectable by 3 h, followed by a continuous maintenance of high mRNA levels up to 18 h. Maximal transcription was obtained with 1000 U/ml of IL-2, which achieved the level observed with known neutrophil-activating factors such as granulocyte macrophage-CSF and Candida albicans. The protein synthesis inhibitor, cycloheximide, had no detectable effect on levels of IL-8 mRNA expression in PMN incubated in medium alone; however, cycloheximide could selectively modulate IL-8 mRNA transcription in PMN, depending on the cytokine used. Cycloheximide did not affect or alter IL-8 mRNA induction in IL-2-treated PMN but abrogated it in granulocyte macrophage-CSF-treated PMN and super-induced the level of IL-8 mRNA in C. albicans-treated PMN. Of significance was the observation that IL-2 has no direct chemotactic effect on PMN, whereas the cell-free supernatants from IL-2-stimulated PMN show potent chemotaxis for freshly isolated PMN, which can be specifically blocked by anti-IL-8 Abs. These findings suggested that the induction of IL-8 gene expression in PMN by IL-2 may be involved in the recruitment of PMN into tissues during local IL-2 therapy in human cancer and in part contribute to tumor rejection.

Interleukin-2 prevention of apoptosis in human neutrophils.

Evidence is presented that interleukin (IL)-2 maintains viability of human polymorphonuclear cells (PMN) in culture by preventing these cells from undergoing programmed cell death (PCD) and induces the synthesis of new RNA and protein. Our laboratory has recently discovered that human PMN constitutively express IL-2 beta receptor and more importantly, PMN are able to respond functionally to IL-2 by enhanced growth inhibitory activity against an opportunistic fungal pathogen, Candida albicans. We now report that IL-2 was able to interfere with the PCD process and reduce the number of apoptotic PMN to < 40% in 72-h culture. Freshly isolated PMN usually underwent a time-dependent aging process and > 80% of PMN cultured in medium alone for 72 h showed morphologic features of PCD as depicted by hematoxylin and eosin staining as well as by electron microscopy. During the PCD process, untreated PMN not only exhibited condensed nuclear structure and decrease in cell size, but also displayed DNA fragmentation. DNA fragmentation in PMN was prevented by IL-2. Prevention of PCD by IL-2 was associated with an increase in new RNA and protein synthesis in PMN, which may reflect cytokine induction, such as tumor necrosis factor, as we have recently shown. Thus, our data expands our current understanding of PMN in that they may be an active component of the immune system, with a longer life-span when activated than expected.