Surgical resection combined with perioperative chemotherapy for a patient with locally recurrent, previously stage IV thymic small-cell carcinoma: A case report.

An 83-year-old Japanese man visited our hospital with dyspnea and general fatigue. Computed tomography (CT) revealed a tumor in the anterior mediastinum, bilateral pleural effusion, pericardial fluid, and multiple liver nodules. We performed a CT-guided tumor biopsy, and the patient was diagnosed with thymic small-cell carcinoma, Masaoka-Koga stage classification IVb. The patient received four cycles of carboplatin and etoposide, and all lesions disappeared on CT. However, after 6 months, CT revealed a recurrent tumor in the anterior mediastinum. After one cycle of rechallenge chemotherapy, we performed extended total thymectomy followed by another three cycles of chemotherapy. More than 2.5 years after the last chemotherapy session, the patient's carcinoma did not recur. Thus, this case suggests that salvage surgery may be a treatment option for local recurrence of thymic carcinoma after complete remission with chemotherapy, even in patients with stage IV cancer.

Radiation therapy induces an abscopal effect and upregulates programmed death-ligand 1 expression in a patient with non-small cell lung cancer.

Radiation therapy (RT) activates the antigen presentation of dendritic cells and priming of cancer-specific cytotoxic CD8+ T cells, occasionally resulting in a systemic immune response to the tumor outside of the treatment field. The phenomenon of tumor regression at the site distant from irradiated fields is known as the abscopal effect. Several case reports have indicated a potential role of RT in overcoming primary and acquired resistance against immune checkpoint inhibitors in non-small cell lung cancer (NSCLC) and melanoma patients. We herein report an NSCLC patient who developed acquired resistance to an RT-induced abscopal effect and subsequently experienced reactivation of the systemic antitumor immune response by pembrolizumab, an antiprogrammed death 1 antibody. In this case, RT not only induced an abscopal effect but also upregulated the programmed death-ligand 1 expression outside of the irradiated field when the patient developed resistance to the abscopal effect. This case can facilitate our understanding of the mechanism underlying the RT-induced systemic immune response against cancer cells and adaptive resistance mechanism of cancer cells from immune surveillance. These findings highlight the promising results of current clinical trials combining RT and immune checkpoint inhibitors. Ongoing clinical trials will further establish evidence supporting combination therapy with RT and immune checkpoint inhibitors.

Wake-up stroke: incidence, risk factors and outcome of acute stroke during sleep in a Japanese population. Takashima Stroke Registry 1988-2003.

Characterization of the time of stroke onset has been plagued by the problem of determining the time of the onset of events that are detected when the patient awakens. Our aim was to evaluate the characteristics, risk factors and acute fatality associated with wake-up stroke. Data was obtained from Takashima Stroke Registry covering approximately 55,000 residents in central Japan. During the period 1988-2003, information about the situation at stroke onset was available for 897 cerebral infarction (CI) and 335 intracerebral hemorrhage (ICH) events. Differences in characteristics and outcome between stroke during sleep and stroke while awake were explored. Among CI and ICH cases, 9.7 and 11.9% suffered from stroke during sleep, respectively. Hypertension and experiencing a severe event were associated with stroke during sleep among CI. Smoking and experiencing a severe event were associated with stroke during sleep and a drinking history reduced the chance of stroke during sleep among ICH. Acute fatality risks did not differ between stroke during sleep and stroke while awake among both CI and ICH cases. About 1 in 10 stroke patients had an onset of stroke during sleep. Hypertensive, smoker and clinically more severely affected patients had a higher prevalence of stroke during sleep. There were no differences between the 2 groups with respect to acute-case fatality.

Association of lifestyle factors, polymorphisms in adiponectin, perilipin and hormone sensitive lipase, and clinical markers in Japanese males.

According to recent genome-wide association studies, a number of single nucleotide polymorphisms is reported to be associated with diseases or several clinical markers. Among them, adiponectin (ADIPOQ) and perilipin (PLIN) polymorphisms are major factors of obesity. However, the association between lifestyle factor, these polymorphisms and obesity-related clinical markers in Japanese is not well researched. Therefore, the aim of present study is to investigate the association between lifestyle factor, polymorphisms of lipid metabolic genes, and clinical markers in 148 middle-aged Japanese males. The study revealed that ADIPOQ 45 T>G and ADIPOQ 276 G>T genotypes were significantly associated with triglyceride, total cholesterol, hemoglobin A1c (HbA1c) in blood and body mass index (BMI). PLIN4 11482 G>A and hormone sensitive lipase (LIPE)-60 C>G genotypes were respectively associated with BMI and serum triglyceride. Not only genetic factors but also lifestyle factors influence several clinical markers. The BMI of subjects who like sweets and have the GG allele in ADIPOQ 276 G>T was higher than that of subjects who don't like sweets. The habit of eating fruits and fish affected low-density lipoprotein-cholesterol of the GT allele and HbA1c of the TT allele in ADIPOQ 276 G>T. Those findings indicate improvement and conservation of lifestyle depending on genetic predisposition in ADIPOQ, PLIN and LIPE should be encouraged.

Circaseptan variation in case-fatality rate for patients with acute subarachnoid hemorrhage (Takashima Stroke Registry 1988-2003).

We explored the circaseptan variation in 28-day case-fatalities for patients with subarachnoid hemorrhage (SAH) across days of the week. Data were obtained from the Takashima Stroke Registry, which covers approximately 50000 residents of central Japan. There were 169 first-ever SAH cases registered during the period 1988-2003 (68 in males, 101 in females). We divided the SAH cases into two groups according to the day on which the SAH occurred: "weekend" and "weekday". The 28-day case-fatality rate and 95% confidence interval (CI) were calculated. Multiple logistic regression analysis was used to calculate the adjusted odds ratio (95% CI) for weekday fatalities by entering all relevant patient-level variables into the model. The 28-day case-fatality rate for SAH was higher on weekdays (51.7%) than on weekends (32.6%; odds ratio 2.19; 95% CI: 1.10-4.49). The differences in fatality rate persisted after adjustment for age, sex, severity, family history of stroke and patient history of hypertension, diabetes mellitus, dyslipidemia, drinking and smoking. We observed a circaseptan variation in fatalities from SAH, with higher fatality rates during weekdays in our study population.

Pregnancy outcome after magnetic resonance-guided focused ultrasound surgery (MRgFUS) for conservative treatment of uterine fibroids.

OBJECTIVE: To report all pregnancies to date after magnetic resonance-guided focused ultrasound surgery (MRgFUS) for the conservative treatment of clinically significant uterine fibroids. DESIGN: Prospective registry of all known pregnancies occurring after MRgFUS maintained by the device manufacturer and reported to the Food and Drug Administration. SETTING: World experience of pregnancies after treatment with reports from 13 sites in seven countries. PATIENT(S): Fifty-one reproductive-age women with uterine leiomyomas. INTERVENTION(S): Women underwent MRgFUS treatment for symptomatic uterine leiomyomas before this report. MAIN OUTCOME MEASURE(S): Pregnancy outcomes and complications. RESULT(S): Fifty-four pregnancies in 51 women have occurred after MRgFUS treatment of uterine leiomyomas. The mean time to conception was 8 months after treatment. Live births occurred in 41% of pregnancies, with a 28% spontaneous abortion rate, an 11% rate of elective pregnancy termination, and 11 (20%) ongoing pregnancies beyond 20 gestational weeks. The mean birth weight was 3.3 kg, and the vaginal delivery rate was 64%. CONCLUSION(S): Preliminary pregnancy experience after MRgFUS is encouraging, with a high rate of delivered and ongoing pregnancies.

Decreasing margins to the uterine serosa as a method for increasing the volume of fibroids ablated with magnetic resonance-guided focused ultrasound surgery.

OBJECTIVE: To demonstrate the safety of magnetic resonance-guided focused ultrasound surgery (MRgFUS) treatments regardless of the distance between the treatment region and the uterine serosa. STUDY DESIGN: 83 pre-menopausal women with symptomatic uterine fibroids were treated with MRgFUS in 88 treatments. Treatment data was analyzed, measuring the distance between the treatment spots (sonications) and the serosa. Patients were followed up for 1 year and adverse events were collected. RESULTS: 79% and 37% of the sonications were less than 15 mm and 10 mm from the serosa, respectively. Treatment was always confined to the fibroid capsule. There were no unexpected or serious adverse events. CONCLUSION: Reducing the margin between the fibroid treatment area and the uterine serosa, when possible, enables MRgFUS treatment of greater fibroid volume, while maintaining a high safety profile. Special attention should be paid when the uterus lies adjacent to other sensitive organs to avoid unintentional heating of these organs, using the planning and real-time MR images.

High-throughput evaluation of quiescent hematopoietic progenitor cells using a micro-multiwell plate.

Conventional assays for hematopoietic progenitor cells (HPCs) require long-term culturing, a labor-intensive procedure, and technique proficiency. We aimed to develop a high-throughput method to determine frequency of quiescent primitive HPCs by a combination of the micro-multiwell plate and 5-fluorouracil (5-FU) treatment. The micro-multiwell plate was made of a silicone sheet with a 6 x 6 array of 1-mm diameter holes and a glass substrate. To enrich primitive HPCs in a CD34 population, CD34 cells and stromal cells were applied to micro-multiwells and cultured in the presence of 5-FU for 2 days. The quiescent primitive HPCs that survived after 5-FU treatment were then expanded with cytokines in the absence of 5-FU for a further 10 days. After culturing, cells were immunostained and the number of primitive HPCs in inoculated CD34 cells was estimated from fluorescent intensity for each well under a stereoscopic fluorescent microscope. The frequencies of primitive HPCs correlated well with frequencies of cobblestone area-forming cells for two CD34 cell lots. Our method allows high-throughput screening for primitive HPCs in CD34 cells.

Higher stroke incidence in the spring season regardless of conventional risk factors: Takashima Stroke Registry, Japan, 1988-2001.

BACKGROUND AND PURPOSE: Seasonal variation in stroke incidence was examined using 14-year stroke registration data in a Japanese population. We also examined if this variation was modified by conventional stroke risk factors hypertension, diabetes mellitus, drinking, and smoking. METHODS: Data were obtained from the Takashima Stroke Registry, which covers a stable population of approximately 55,000 in Takashima County in central Japan. There were 1665 (men, 893; women, 772) registered first-ever stroke cases during 1988 to 2001. The average age of stroke onset for men and women patients was 69.4 and 74.2 years, respectively. Incidence rates (per 100 000 person-years) and 95% CI were calculated by gender, age, and stroke subtype for winter, spring, summer, and autumn. After stratifying patients by their risk factor history, the OR (with 95% CI) of having a stroke in autumn, winter, and spring were calculated, with summer serving as a reference. RESULTS: Among the seasons, stroke incidence per 100,000 person-years was highest in the spring (231.3; 95% CI, 211.1 to 251.5). Spring incidence was highest in both men (240.8; 95% CI, 211.5 to 270.2) and women (222.1; 95% CI, 194.4 to 249.9), and in subjects younger than 65 years (72.6; 95% CI, 60.0 to 85.3) and 65 years or older (875.9; 95% CI, 787.5 to 964.3). Among stroke subtypes, spring incidence was highest for cerebral infarction (154.7; 95% CI, 138.2 to 171.2) and cerebral hemorrhage (53.7; 95% CI, 44.0 to 63.4). The spring excess in stroke incidence was observed regardless of the presence or absence of the risk factor histories. CONCLUSIONS: Stroke incidence appears to be highest in the spring among a Japanese population regardless of conventional risk factor history. Factors that explain this excess need further investigation.

Non-invasive magnetic resonance imaging-guided focused ultrasound treatment for uterine fibroids - early experience.

OBJECTIVE: To describe early results regarding efficacy and safety of magnetic resonance imaging-guided focused ultrasound surgery (MRgFUS) for the treatment of uterine leiomyomas among a population of Japanese women. STUDY DESIGN: In this single site study, 48 Japanese women, over 18 years of age, who were candidates for surgical intervention due to symptomatic fibroids, were recruited. Fifty-five uterine fibroids were treated by MRgFUS and followed up for 12 months. RESULTS: During the 12-month follow-up period, two patients (4%) required surgical interventions, and two patients required additional drug treatment for fibroids. The average reduction in fibroid volume determined by MR imaging at 6 months after treatment was 33%. This volume reduction is correlated with the fibroid's treated volume. No serious complications were recorded during the treatments or follow-up period. CONCLUSION: MRgFUS can safely be used to non-invasively treat symptomatic uterine fibroids and avoid the need for surgical intervention in the short term. With large treatment volumes, MRgFUS also results in significant fibroid shrinkage in a relatively short time. Additional follow-up is needed to determine the long-term durability of this promising non-invasive approach.

Clonal analysis of hematopoiesis-supporting activity of human mesenchymal stem cells in association with Jagged1 expression and osteogenic potential.

Human mesenchymal stem cells (hMSCs) are promising feeder cells for expanding hematopoietic stem cells (HSCs), but their potential is heterogeneous. We examined the hematopoiesis-supporting activity of hMSC at the clonal level in relation to the osteogenic potential and gene expression. Hematopoiesis-supporting activities of stably immortalized clonal hMSC lines were evaluated by the expansion of CD34+CD38- cells after 7-day coculture with human cord blood-derived CD34+ cells. Six of 16 clones expanded the numbers of CD34+CD38- cells >500-fold. These hematopoiesis-supportive clones also showed high gene expression of Jaggedl, a Notch ligand, as well as high potential to deposit calcium after osteogenic induction. Thus, osteogenic hMSC clones may provide proper microenvironments for HSC expansion, ultimately conveying self-renewal signals to HSCs via the Notch pathway. However, they lost hematopoiesis-supporting activity after osteogenic differentiation. The hematopoiesis-supportive clones are potentially useful for hematopoietic microenvironment studies and as components of a coculture system for expansion of HSCs, free from contamination by xenogeneic pathogens.

Increase of stroke incidence after weekend regardless of traditional risk factors: Takashima Stroke Registry, Japan; 1988-2003.

BACKGROUND AND PURPOSE: The study purpose was to identify patterns of variation in stroke incidence among days of the week and examine if it is modified by conventional stroke risk factors: hypertension, diabetes, drinking and smoking. METHODS: Data were obtained from the Takashima Stroke Registry, which covers a stable population of roughly 55,000 residents of Takashima County in central Japan. A total of 1,773 stroke cases (men: 943 and women: 830) occurred between 1988 and 2003. We divided the days into 3 groups: 'weekend', 'after weekend' and 'rest of the week', and calculated stroke incidence rates and incidence rate ratios. To identify the effect of conventional risk factors on the variation, proportion of differences between observed and expected stroke incidences were considered. RESULTS: The stroke incidence for the after weekend group (250.1 per 100,000 person years, 95% CI: 222.0-278.3) was higher than for the other day groups among men. The after weekend increase was observed mainly among older men aged 65 years or more. Among the stroke subtypes, the incidence for cerebral infarction was highest in the after weekend group (857.2, 95% CI: 730.6-983.8) and was 1.37 times (95% CI: 1.12-1.68) higher than in the rest of the week group. Tendency of after weekend increase was observed regardless of the presence or absence of risk factor history. CONCLUSIONS: Week day variation for stroke was observed predominantly among older men regardless of presence and absence of risk factor history. Information about the weekly trend regarding episode of increased stroke incidence can be used as a surrogate predictor for stroke onset and would be helpful in designing more effective insights for preventive strategies.

TRAF7 sequesters c-Myb to the cytoplasm by stimulating its sumoylation.

Small ubiquitin-related modifiers (SUMOs) are proteins that are posttranslationally conjugated to diverse proteins. The c-myb proto-oncogene product (c-Myb) regulates proliferation and differentiation of hematopoietic cells. PIASy is the only known SUMO E3 ligase for c-Myb. Here, we report that TRAF7 binds to c-Myb and stimulates its sumoylation. TRAF7 bound to the DNA-binding domain of c-Myb via its WD40 repeats. TRAF7 has an E3 ubiquitin ligase activity for self-ubiquitination, but TRAF7 also stimulated the sumoylation of c-Myb at Lys-523 and Lys-499, which are the same sites as those used for PIASy-induced sumoylation. TRAF7 inhibited trans-activation induced by wild-type c-Myb, but not by the sumoylation site mutant of c-Myb. The expression of both c-myb and TRAF7 was down-regulated during differentiation of M1 cells. Endogenous TRAF7 localized to both the cytoplasm and nucleus of M1 cells. Consistent with this, significant amounts of sumoylated c-Myb were found in the cytoplasm of M1 cells, whereas nonsumoylated c-Myb was found predominantly in the nucleus. Overexpressed TRAF7 was localized in the cytoplasm of CV-1 cells, and sequestered c-Myb and SUMO1 in the cytosol, whereas PIASy was localized in the nucleus. Thus, TRAF7 negatively regulates c-Myb activity by sequestering c-Myb to the cytosol via sumoylation.

Effects of imposed bending on microtubule sliding in sperm flagella.

The movement of eukaryotic flagella is characterized by its oscillatory nature. In sea urchin sperm, for example, planar bends are formed in alternating directions at the base of the flagellum and travel toward the tip as continuous waves. The bending is caused by the orchestrated activity of dynein arms to induce patterned sliding between doublet microtubules of the flagellar axoneme. Although the mechanism regulating the dynein activity is unknown, previous studies have suggested that the flagellar bending itself is important in the feedback mechanism responsible for the oscillatory bending. If so, experimentally bending the microtubules would be expected to affect the sliding activity of dynein. Here we report on experiments with bundles of doublets obtained by inducing sliding in elastase-treated axonemes. Our results show that bending not only "switches" the dynein activity on and off but also affects the microtubule sliding velocity, thus supporting the idea that bending is involved in the self-regulatory mechanism underlying flagellar oscillation.

Human chorionic gonadotropin combined with progesterone for luteal support improves pregnancy rate in patients with low late-midluteal estradiol levels in IVF cycles.

PURPOSE: To investigate how late-midluteal estradiol levels relate to the pregnancy outcome in IVF cycles, and to assess whether human chorionic gonadotropin (hCG) for luteal support benefits the pregnancy outcome of patients with low late-midluteal estradiol levels. METHODS: The pregnancy rate of 436 women undergoing first IVF cycles with long protocol and luteal support with progesterone alone were analyzed. Unsuccessful women with low late-midluteal estradiol levels (< 100 pg/mL) proceeded with the exploratory second IVF cycles where they were randomly given with either progesterone alone (P protocol) or hCG +progesterone (P+hCG protocol) for luteal support. RESULTS: Pregnancy rate in women with low late-midluteal estradiol levels was significantly lower compared to that with medium (100-500 pg/mL) and high (> 500 pg/mL) levels (13.3, 26.8, and 36.3%, respectively). P+hCG protocol increased late-midluteal estradiol levels and produced a significantly higher pregnancy rate (31.7%) than P protocol (13.7%). CONCLUSIONS: hCG in combination with progesterone for luteal support was suggested to benefit women undergoing IVF with low late-midluteal estradiol levels.

IgG-mediated signal transduction in canine mastocytoma-derived cells.

BACKGROUND: We have reported canine cutaneous mastocytoma-derived cells named CM-MC sensitized with monomeric IgG released histamine upon anti-IgG stimulation. However, IgG or IgE-mediated signal transduction in the cells remains to be examined. METHODS: Monomeric IgG-binding to cells was measured by flow cytometry using FITC-anti-IgG. IgG-mediated protein tyrosine phosphorylation was studied by Western blotting using anti-phosphotyrosine antibody. We monitored the intracellular Ca(2+) concentration ([Ca(2+)](i)) when IgG-primed cells were activated with anti-canine IgG. Release of Ca(2+) from intracellular stores was analyzed with thapsigargin in the absence of extracellular Ca(2+). The Ca(2+) entry via store-operated Ca(2+) channel from the external environment was characterized using Ba(2+), Ni(2+) and EGTA. Cells sensitized with canine serum abundant in IgG and IgE or heat-inactivated serum were activated by anti-canine IgG or anti-canine IgE. The effect of extracellular Ca(2+) and reaction time on IgG-mediated histamine release was examined. Staurosporine and ER-27319 were used to clarify the IgG-mediated protein tyrosine phosphorylation. RESULTS: Abundant IgG-binding sites on the cell were detected by FACS analysis. Anti-IgG induced rapid protein tyrosine phosphorylation and [Ca(2+)](i) elevation. When extracellular Ca(2+) was excluded by EGTA, a mild and transient increase in [Ca(2+)](i) was observed, indicating the release of Ca(2+) from anti-IgG-sensitive intracellular Ca(2+) stores. The constant Ba(2+) entry from external environment proved the Ca(2+) influx occurred mainly via a store-operated Ca(2+) channel which was inhibited by Ni(2+) and EGTA. Canine serum-sensitized cells showed a rapid and sustained increase in [Ca(2+)](i) upon both anti-IgG and anti-IgE stimulation. The [Ca(2+)](i) elevation induced by anti-IgE was decreased in the cells sensitized with heat-inactivated serum. Histamine release from CM-MCs was absolutely dependent on extracellular Ca(2+), and reached equilibrium within 5 min. Staurosporine inhibited the tyrosine phosphorylation of 38-, 65-, 70-, 80-kD proteins. ER-27319 inhibited the tyrosine phosphorylation of 38- and 70-kD proteins. Staurosporine also inhibited IgG-mediated [Ca(2+)](i) elevation and histamine release in a dose-dependent manner. CONCLUSIONS: Canine cutaneous mastocytoma-derived (CM-MC) cells were activated by both IgG- and IgE-mediated mechanisms. IgG-mediated protein tyrosine phosphorylation and Ca(2+) influx were similar to those mediated by IgE. CM-MC cells are useful for the study of allergic inflammation caused by IgG-dependent mechanisms.

A functional study on CysLT(1) receptors in human eosinophils.

BACKGROUND: The cysteinyl leukotrienes (CysLTs) mediate their biological actions through two receptors: CysLT(1) receptor and CysLT(2) receptor. OBJECTIVE: This study was undertaken to examine the direct effects of CysLTs on eosinophils, such as chemotaxis and degranulation, focusing on CysLT(1). METHODS: Eosinophils were isolated from venous blood from normal volunteers who had no history of allergy (purity >99%). They were subjected to reverse transcription-PCR analysis and flow-cytometric analysis for CysLT(1). Binding assays were performed with [(3)H]LTD(4). Purified eosinophils loaded with Fura-2 acetoxymethyl ester were stimulated with CysLTs, and Ca(2+) influx was measured. Eosinophil migration in response to CysLTs was measured using a 96-well multiwell Boyden chamber. Eosinophils were treated with LTD(4) at 10(-6) M for 60 min followed by incubation for 4 h at 37 degrees C in the presence or absence of IL-5 and eosinophil-derived neurotoxin (EDN) release was evaluated. RESULTS: The expression of the mRNA and protein of CysLT(1) on eosinophils and [(3)H]LTD(4)-specific binding to eosinophils were observed. Neither Th1 cytokine (IFN-gamma) nor Th2 cytokines (IL-4 or IL-5) affected CysLT(1) expression in eosinophils. CysLTs induced an increase in intracellular free Ca(2+) in eosinophils via CysLT(1), as suggested by the efficient inhibition by a CysLT(1) antagonist, pranlukast, in addition to the rank order of potency being LTD(4), LTC(4) and LTE(4). LTD(4) stimulated eosinophils to migrate at 10(-6) M via CysLT(1). LTE(4) also induced significant eosinophil migration at 10(-6) M. LTD(4) enhanced EDN release induced by IL-5 via CysLT(1). CONCLUSION: CysLTs induce migration and enhance degranulation in eosinophils via CysLT(1). Accordingly, interaction of CysLTs and CysLT(1) on eosinophils has the potential to play a prominent role in the pathophysiology of asthma.

Evaluation of the disintegration time of rapidly disintegrating tablets via a novel method utilizing a CCD camera.

Many kinds of rapidly disintegrating or oral disintegrating tablets (RDT) have been developed to improve the ease of tablet administration, especially for elderly and pediatric patients. In these cases, knowledge regarding disintegration behavior appears important with respect to the development of such a novel tablet. Ordinary disintegration testing, such as the Japanese Pharmacopoeia (JP) method, faces limitations with respect to the evaluation of rapid disintegration due to strong agitation. Therefore, we have developed a novel apparatus and method to determine the dissolution of the RDT. The novel device consists of a disintegrating bath and CCD camera interfaced with a personal computer equipped with motion capture and image analysis software. A newly developed RDT containing various types of binder was evaluated with this protocol. In this method, disintegration occurs in a mildly agitated medium, which allows differentiation of minor distinctions among RDTs of different formulations. Simultaneously, we were also able to detect qualitative information, i.e., morphological changes in the tablet during disintegration. This method is useful for the evaluation of the disintegration of RDT during pharmaceutical development, and also for quality control during production.

Cytokine-mediated regulation of CXCR4 expression in human neutrophils.

Several lines of evidence have suggested that a CXC chemokine receptor 4 (CXCR4)/stromal cell-derived factor-1 [SDF-1; CXC chemokine ligand 12 (CXCL12)] pair is involved in baseline trafficking of leukocytes into extravascular tissues and that modulation of surface CXCR4 expression may represent an alternative mechanism for control of cell-specific biological responses to SDF-1/CXCL12. We explored the regulation of CXCR4 expression by cytokines in polymorphonuclear neutrophils (PMNs). No significant surface expression of CXCR4 in freshly isolated PMNs was detected, but expression became apparent gradually during incubation. SDF-1alpha/CXCL12 initiated Ca2+ mobilization and migratory responses in 20 h cultured PMNs. The surface CXCR4 expression was suppressed most potently by interferon-gamma (IFN-gamma). IFN-alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), and G-CSF also inhibited spontaneous CXCR4 expression. Real-time, quantitative PCR experiments revealed that a spontaneous increase and an IFN-gamma-mediated decrease in surface CXCR4 paralleled changes in the CXCR4 mRNA level. These results on PMNs support the argument that the SDF-1 (CXCL12)/CXCR4 system is regulated by cell type-specific mechanisms.