Anti-inflammatory potential of remimazolam: A laboratory and clinical investigation.

BACKGROUND: Anesthetic agents, particularly intravenous anesthetics, may affect immune function and tumorigenic factors. We herein investigated whether the anti-inflammatory effects of anesthetic agents are attributed to their antioxidant properties. The antioxidant and anti-inflammatory effects of remimazolam, a new anesthetic, remain unclear. We hypothesized that remimazolam exerts anti-inflammatory effects due to its antioxidant properties, which may affect the postoperative inflammatory response. This retrospective clinical study examined this hypothesis using laboratory and clinical approaches. METHODS: The antioxidant effects of remimazolam and dexmedetomidine were assessed by electron spin resonance (ESR) spectroscopy, and postoperative inflammatory responses were compared in 143 patients who underwent transcatheter aortic valve replacement at Kindai University Hospital between April 2021 and December 2022. The primary endpoint was the presence or absence of the antioxidant effects of the anesthetics themselves using ESR. RESULTS: Remimazolam at clinical concentrations exerted antioxidant effects, whereas dexmedetomidine did not. Increases in C-reactive protein (CRP) levels on POD3 from preoperative values were significantly smaller in the remimazolam group than in the dexmedetomidine group (1.33 ± 1.29 vs. 2.17 ± 1.84, p = .014). CONCLUSIONS: Remimazolam exerted stronger anti-inflammatory effects than dexmedetomidine, and these effects were enhanced by its antioxidant properties, which may have affected postoperative CRP production.

Predictors of post-extubation stridor in patients on mechanical ventilation: a prospective observational study.

The cuff leak test (CLT) has been widely accepted as a simple and noninvasive method for predicting post-extubation stridor (PES). However, its accuracy and clinical impact remain uncertain. We aimed to evaluate the reliability of CLT and to assess the impact of pre-extubation variables on the incidence of PES. A prospective observational study was performed on adult critically ill patients who required mechanical ventilation for more than 24 h. Patients were extubated after the successful spontaneous breathing trial, and CLT was conducted before extubation. Of the 191 patients studied, 26 (13.6%) were deemed positive through CLT. PES developed in 19 patients (9.9%) and resulted in a higher reintubation rate (8.1% vs. 52.6%, p < 0.001) and longer intensive care unit stay (8 [4.5-14] vs. 12 [8-30.5] days, p = 0.01) than patients without PES. The incidence of PES and post-extubation outcomes were similar in patients with both positive and negative CLT results. Compared with patients without PES, patients with PES had longer durations of endotracheal intubation and required endotracheal suctioning more frequently during the 24-h period prior to extubation. After adjusting for confounding factors, frequent endotracheal suctioning more than 15 times per day was associated with an adjusted odds ratio of 2.97 (95% confidence interval, 1.01-8.77) for PES. In conclusion, frequent endotracheal suctioning before extubation was a significant PES predictor in critically ill patients. Further investigations of its impact on the incidence of PES and patient outcomes are warranted.

Midazolam suppresses the lipopolysaccharide-stimulated immune responses of human macrophages via translocator protein signaling.

BACKGROUND: Benzodiazepines are widely used for anesthesia and sedation and have immunomodulatory properties that may negatively influence clinical outcomes; however, the cellular targets and intermediary signaling pathways involved are unclear. We examined the immunomodulatory effects of the benzodiazepine midazolam on human macrophages and associated molecular mechanisms. METHODS: We analyzed effects of midazolam pretreatment on lipopolysaccharide (LPS)-induced upregulation of the costimulatory molecule CD80 and secretion of the pro-inflammatory factors interleukin-6 (IL-6), tumor necrosis factor-α, interleukin-10, and nitric oxide (NO) in the human monocyte-macrophage cell line THP-1 and in peripheral monocyte-derived macrophages (PMDMs). The effects of midazolam on NF-κB, IκBα protein, and mitogen-activated protein kinase (MAPK) activation were analyzed in THP-1 cells. We analyzed the involvement of translocator protein (TSPO) in the immunomodulatory effects of midazolam using TSPO ligands. The role of TSPO was investigated using THP-1 cells overexpressing TSPO and THP-1 cells with TSPO knockdown through transfection with small interfering RNA for TSPO. RESULTS: Midazolam suppressed LPS-induced upregulation of CD80 and release of IL-6 and NO in THP-1 cells and PMDMs. Additionally, midazolam suppressed the activation of NF-κB/AP-1 and MAPKs in human THP-1 cells. The assessed synthetic TSPO ligands showed the same inhibitory effects on macrophage activation as midazolam. Macrophages overexpressing TSPO exhibited enhanced susceptibility to immunosuppression by midazolam, and macrophages lacking TSPO expression exhibited reduced effects of midazolam. CONCLUSION: Midazolam inhibits LPS-stimulated immune responses in human macrophages by activating TSPO signaling. Suppression of macrophage activity may contribute to deleterious side effects of benzodiazepines reported in critically ill patients.

Haloperidol Suppresses NF-kappaB to Inhibit Lipopolysaccharide-Induced Pro-Inflammatory Response in RAW 264 Cells.

BACKGROUND Haloperidol, a tranquilizing agent, is administered both to treat symptoms of psychotic disorders and to sedate agitated and delirious patients. Notably, haloperidol has been suggested to inhibit the immune response through unknown mechanisms. We hypothesized that the sedative modulates the immune response via NF-κB. MATERIAL AND METHODS Using flow cytometry, we analyzed the effects of haloperidol on expression CD80 and CD86 in RAW 264 cells and in primary macrophages derived from bone marrow. Secretion of interleukin (IL)-1ß, IL-6, and IL-12 p40 was measured by enzyme-linked immunosorbent assay. In addition, NF-κB activation was evaluated using a reporter assay based on secretory embryonic alkaline phosphatase. Finally, synthetic antagonists were used to identify the dopamine receptor that mediates the effects of haloperidol. RESULTS Haloperidol inhibited NF-κB activation, and thereby suppressed expression of CD80, as well as secretion of IL-1ß, IL-6, and IL-12 p40. CD80 and IL-6 levels were similarly attenuated by a D2-like receptor antagonist, but not by a D1-like receptor antagonist. CONCLUSIONS The data strongly suggest that haloperidol inhibits the immune response by suppressing NF-kB signaling via the dopamine D2 receptor.

Efficacy and Safety of Landiolol Compared to Amiodarone for the Management of Postoperative Atrial Fibrillation in Intensive Care Patients.

OBJECTIVE: The authors assessed the efficacy and safety of landiolol, an ultra-short-acting beta-blocker, with those of amiodarone in the restoration of sinus rhythm for postoperative atrial fibrillation (POAF) in intensive care unit (ICU) patients. DESIGN: A retrospective data analysis. SETTING: Data were collected from patients admitted to the ICU in a single university hospital between 2012 and 2015. PARTICIPANTS: Records of a total of 276 patients who developed POAF after ICU admission were collected from hospital records. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Treatment success was defined as restoration of sinus rhythm without concomitant therapy within 24 hours of treatment and lasting for more than an hour. The landiolol dosage was in the range of 0.7 µg/kg/min-to-2.5 µg/kg/min. The authors compared a total of 55 patients with POAF who received either landiolol (n = 32) or intravenous amiodarone (n = 23) in the ICU. The major findings were that the median time required for conversion to sinus rhythm was shorter in landiolol patients compared with amiodarone patients (75 v 150 min respectively, p = 0.0355). However, treatment success rates did not differ significantly after 24 hours (odds ratio 1.25, 95% confidence interval 0.17-9.09, p = 0.60). Adverse events with bradycardia leading to drug discontinuation were seen only in the patients receiving amiodarone (n = 3, p = 0.032). CONCLUSIONS: Landiolol achieved swift and safe restoration of sinus rhythm in ICU patients with POAF and could be considered as a favorable drug choice over amiodarone in such patients.

Haloperidol suppresses murine dendritic cell maturation and priming of the T helper 1-type immune response.

BACKGROUND: Haloperidol has immunomodulatory effects when used to treat patients with schizophrenia and also is used to sedate critically ill patients in the intensive care unit. Although the mechanism by which haloperidol affects immune function is unclear, one possibility is that it alters dendritic cell (DC) function. DCs are potent antigen-presenting cells that influence the activation and maturation of T lymphocytes. In this study, we investigated the in vitro and in vivo immunomodulatory effects of haloperidol on DC-mediated immune responses. METHODS: Using bone marrow-derived DCs in cell culture, we evaluated the effect of haloperidol on expression of costimulatory molecules (CD80 and CD86), major histocompatibility complex class ΙІ molecules, and the DC maturation marker CD83. DC culture supernatants also were evaluated for interleukin-12 p40 levels. In addition, we analyzed the effect of haloperidol on a mixed cell culture containing DCs and lymphocytes and measured the secretion of interferon-γ in the culture supernatants. We also assessed the in vivo effects of haloperidol on hapten-induced contact hypersensitivity responses. RESULTS: Haloperidol inhibited the expression of CD80, CD86, major histocompatibility complex class ΙІ, and CD83 molecules on DCs and the secretion of interleukin-12p40 in DC culture supernatants. In mixed cell cultures containing both T cells (CD4 and CD8α) and DCs, haloperidol-treated DCs suppressed the proliferation of allogeneic T cells and effectively inhibited the production of interferon-γ. In vivo, haloperidol reduced hapten-induced contact hypersensitivity responses. Furthermore, an antagonist to D2-like receptor suppressed the maturation of DCs in a manner similar to haloperidol. CONCLUSIONS: The results of our study suggest that haloperidol suppresses the functional maturation of DCs and plays an important role in the inhibition of DC-induced T helper 1 immune responses in the whole animal. Furthermore, the effect of haloperidol on DCs may be mediated by dopamine D2-like receptors. Together, these results demonstrate that administration of haloperidol suppresses DC-mediated immune responses.

Perioperative fluid balance affects staging of acute kidney injury in postsurgical patients: a retrospective case-control study.

BACKGROUND: Although Acute Kidney Injury Network (AKIN) staging is widely used, it has been suggested that classification using serum creatinine levels, which fluctuate because of fluid balance, is not always appropriate for acute kidney injury (AKI) detection. We hypothesized that some patients are misdiagnosed as having no AKI due to dilution resulting from intraoperative infusion, and have worse outcomes than typical patients with no AKI. METHODS: We retrospectively selected patients who did not fulfill the AKI criteria from those who underwent cardiac surgery and remained in an intensive care unit (ICU) for ≥7 days. The patients were divided into two groups: those with AKI (AKI group) and those without AKI (no-AKI group), classified using serum creatinine levels adjusted for fluid balance during the perioperative period. We compared the characteristics and outcomes of the two groups. RESULTS: After adjustment for serum creatinine, 7 of 26 patients were categorized as having AKI. The AKI group had significantly fewer ventilator-free days during a 28-day period and significantly longer ICU stays than the no-AKI group (5.86 ± 10.0 days vs. 15.6 ± 9.71 days, respectively, P = 0.050; 36.4 ± 20.6 days vs. 14.9 ± 10.7 days, respectively, P = 0.033). CONCLUSION: Adjustment of creatinine level for perioperative fluid balance could improve the accuracy of AKI diagnosis after cardiac surgery.

Influence of humidification on comfort during noninvasive ventilation with a helmet.

OBJECTIVE: To evaluate optimal humidifier water temperature when using a helmet for noninvasive ventilation. METHODS: Twenty-eight healthy individuals underwent 8 cm H2O CPAP ventilation with FIO2 of 0.21 and 0.5. Each was sequentially tested in the following order: using the helmet without humidification at ambient temperature; with humidification with unheated chamber water; and with humidification with the chamber water at 31°C, 34°C, and 37°C. At each setting, after a 20 min stabilization period, measurements were taken. Comfort level at each setting was evaluated using a visual analog scale rated zero (least comfortable) to 10 (most comfortable). RESULTS: Temperature and relative and absolute humidity inside the helmet increased; however, the comfort scores significantly decreased as the humidification chamber water temperature increased. Regardless of the FIO2, statistically significantly highest comfort scores were obtained when humidification water, with and without active humidification, was at ambient temperature. Unacceptable absolute humidity was obtained only without humidification at room temperature when FIO2 was 0.5. CONCLUSIONS: With the clinical use of a helmet, for patient comfort and mucosal humidification during CPAP, the most desirable conditions are likely to be obtained by humidifying without heating, that is by leaving the water in the humidifier chamber at room temperature.

Midazolam suppresses maturation of murine dendritic cells and priming of lipopolysaccharide-induced t helper 1-type immune response.

BACKGROUND: Dendritic cells (DCs), as antigen-presenting cells, play a key role in the induction and regulation of adaptive immune response. Midazolam is reported to have immunomodulatory properties that affect immune cells. However, the effect of midazolam on DCs has not been characterized. We examined the immunomodulatory properties of midazolam on DC-mediated immune response. METHODS: After allowing murine bone marrow-derived DCs induced by granulocyte macrophage colony stimulating factor to mature, we analyzed their expression of costimulatory molecules (CD80 and CD86), major histocompatibility complex class II molecules, and the secretion of interleukin-12 p40. In vitro, we evaluated the effect of midazolam on maturing DCs in mixed cell cultures containing DCs and T cells. In vivo, we investigated the contact-hypersensitivity response. RESULTS: Midazolam suppressed the expression of CD80, CD86, and major histocompatibility complex class II molecules from murine DCs. Treated with midazolam, DCs also secreted less interleukin-12 p40. In mixed cell cultures with CD3-positive T cells, midazolam-treated DCs showed less propensity to stimulate the proliferation of CD3-positive T cells and the secretion of interferon-γ from CD4-positive T cells. Midazolam-treated DCs impaired the induction of contact-hypersensitivity response. Treatment with ligands for peripheral benzodiazepine receptor inhibited the up-regulation of CD80 during DC maturation. CONCLUSION: Midazolam inhibits the functional maturation of murine DCs and interferes with DC induction of T helper 1 immunity in the whole mouse. In addition, it appears that the immunomodulatory effect of midazolam is mediated via the action of midazolam on the peripheral benzodiazepine receptor.

[Tracheal compression caused by hematoma and felt strips around an anastomosis site following repair of thoracic aneurysm: a case report].

Respiratory complication is common after a repair of thoracic aneurysm, although tracheal compression caused by hematoma and felt strips following surgery is a rare cause. We report the case of a patient who experienced difficult weaning from ventilator after a repair of a thoracic aortic aneurysm and was diagnosed as a tracheal compression outside of trachea revealed by bronchoscopy and chest CT scan. Re-operation was successfully performed to relieve the compression under monitoring by bronchoscopy. Patient was disconnected from the ventilator three weeks after the reoperation and transferred to a rehabilitation hospital.

Ketamine inhibits maturation of bone marrow-derived dendritic cells and priming of the Th1-type immune response.

BACKGROUND: Dendritic cells (DCs) play a key role as antigen-presenting cells and growing evidence suggests that DCs influence T-cell activation and regulate the polarity of the immune response. Ketamine has been reported to have immunomodulatory properties that affect immune cells, including macrophages and natural killer cells. However, the effect of ketamine on DCs has not been characterized. We examined the immunomodulation of DCs by ketamine. METHODS: We used bone marrow-derived DCs induced by granulocyte-monocyte-colony stimulating factor and interleukin (IL)-4 from bone marrow and analyzed the expression of costimulatory molecules (CD40, CD80, and CD86), major histocompatibility complex class II molecules, and secretion of IL-12p40. Furthermore, we evaluated the immune response in mixed cell cultures of DCs and T cells and the contact hypersensitivity response in a whole animal. RESULTS: Ketamine suppressed the expression of CD40, CD80, and major histocompatibility complex class II molecules in DCs. DCs treated with ketamine also secreted less IL-12p40 and displayed greater endocytosis. In mixed cell cultures with CD4+ T cells and DCs, ketamine-treated DCs showed less propensity to stimulate the proliferation of CD4+ T cells and the secretion of interferon from CD4+ T cells. Furthermore, ketamine-treated DCs impaired the induction of a cell-mediated immune response. CONCLUSION: Our findings suggest that ketamine inhibits the functional maturation of DCs and interferes with DC induction of Th1 immunity in the whole animal. These novel findings provide new insight into the immunopharmacological role of ketamine.

[Two cases of transfusion-related acute lung injury following massive transfusion during the perioperative period].

Transfusion-related acute lung injury (TRALI) is a serious complication of transfusion of blood and blood components. TRALI is reported to be the most common cause of transfusion-associated death. TRALI has increasingly become known in the medical community. However, TRALI has been overlooked frequently because of poor knowledge of medical staffs. We report two cases of TRALI after massive transfusion due to massive bleeding during cardiovascular surgery. In the perioperative period, the diagnosis of TRALI is difficult to make because of coexistence of various factors leading to hypoxia. Thus, in this report, we discuss the management of these two cases focusing upon the differential diagnosis of TRALI.

Analgesic effect of dexmedetomidine in a patient with herpetic stomatitis after living-donor lung transplantation.

A 31-year-old woman suffering from bronchiolitis obliterans received bilateral living-donor lung transplantation to treat end-stage respiratory failure. After 5 days' mechanical ventilation, the patient was successfully extubated. During mechanical ventilation, the patient was sedated with a continuous intravenous infusion of propofol and dexmedetomidine (DEX). To assuage postoperative pain, morphine was infused, first intravenously, then epidurally. The administration of DEX was continued after extubation to prevent agitation. After the administration of epidural morphine was discontinued on day 10 in the intensive care unit (ICU), the patient complained of pain in the oral cavity. Greater pain was reported after the discontinuation of DEX, and symptoms of tachycardia and dyspnea appeared. A dermatologist diagnosed the oral symptoms as herpetic stomatitis, and a course of treatment with aciclovir was begun. A continuous infusion of DEX was again started on the same day, and was continued until ICU day 13. During the administration of DEX, the oral cavity pain was bearable. The patient was successfully discharged from the ICU on ICU day 13. We conclude that DEX could be used to provide analgesia for herpetic stomatitis after living-donor lung transplantation, at a dosage that achieves appropriate sedation.

Long-term results of the open stent-grafting technique for extended aortic arch disease.

OBJECTIVE: This report elucidates the long-term safety and effectiveness of extended aortic arch replacement with an open stent-grafting technique from our 12 years of experience. METHODS: From 1994 to 2004, 126 patients (mean age 67.8 years) with different pathologic conditions of the aortic arch with extension to the descending aorta (57 dissections [acute/chronic = 31/26] and 69 aneurysms) were operated on with an open stent-grafting technique. During deep hypothermic circulatory arrest with selective cerebral perfusion, the stent graft was delivered through the transected proximal aortic arch, and arch replacement with a 4-branched prosthesis was performed. RESULTS: Operative mortality within 30 days was 3.2%. Perioperative morbidity included 7 (5.6%) strokes and 8 (6.3%) spinal injuries (paraplegia in 3, transient paraparesis in 5). Sixty-three percent of the patients were extubated within 24 hours. In long-term follow-up (mean 60.4 +/- 36.5 months, maximum 153 months), survival was 81.1%, 63.3%, and 53.7% at 1, 5, and 8 years. Five (3.9%) late endoleaks were observed but treated with successful additional endovascular repair. Freedom from endoleaks was 98.0%, 91.1%, and 91.1% for 1, 5, and 8 years, respectively. CONCLUSION: Long-term observation showed safety and good durability of the open stent-grafting technique for aortic arch disease. This technique could be an attractive treatment option for aortic arch aneurysm with distal extension and aortic dissection requiring aortic arch replacement.

Rhabdomyolysis induced by Pseudomonas aeruginosa sepsis.

We describe advanced hemodynamic insufficiency and remarkably high myoglobinemia in a 77-year-old man who was admitted to the intensive care unit after total aortic arch replacement. Serum myoglobin showed an unusually high value (peak value, 155,030 ng x ml(-1)). The patient died of sepsis and untreatable metabolic acidosis. Pseudomonas aeruginosa was detected in blood culture specimens after his death. On histopathological examination, dense congregations of gram-negative bacilli were present in clots in blood vessels, while congregations of gram-negative bacilli around the circumference of small blood vessels were particularly apparent in every specimen examined. Moreover, a generalized breakdown of muscle fibers, consistent with findings of rhabdomyolysis, was observed in muscle tissue throughout the body.

Vocal cord paralysis after surgery to the descending thoracic aorta via left posterolateral thoracotomy.

Vocal cord paralysis is one of the frequently encountered complications after aortic surgery. However, reports of vocal cord paralysis after aortic surgery have been limited. In a retrospective cohort study of vocal cord paralysis after aortic surgery at a general hospital, we sought factors related to its development after aortic surgery to the descending thoracic aorta via left posterolateral thoracotomy. We reviewed data for a total of 69 patients who, between 1989 and 1995, underwent aortic surgery to the descending thoracic aorta. We assessed factors associated with the development of vocal cord paralysis and postoperative complications. Postoperative vocal cord paralysis appeared in 19 patients. Multiple logistic regression analysis revealed two risk factors for vocal cord paralysis: chronic dilatation of the aorta at the left subclavian artery (odds ratio = 8.67) and anastomosis proximal to the left subclavian artery (odds ratio = 17.7). The duration of mechanical ventilation was significantly prolonged for patients with vocal cord paralysis. Certain surgical factors associated with left subclavian artery increase the risk of vocal cord paralysis after surgery on the descending thoracic aorta. Vocal cord paralysis after aortic surgery did not increase aspiration pneumonia but was associated with pulmonary complications.

Vocal cord paralysis after aortic arch surgery: predictors and clinical outcome.

OBJECTIVE: This study is retrospective cohort study of data on vocal cord paralysis after aortic arch surgery collected during 14 years at a general hospital. We investigated factors in the development of vocal cord paralysis after aortic arch surgery and the effect of vocal cord paralysis on clinical course and outcome. METHODS: We reviewed data for 182 patients who underwent aortic arch surgery for aortic arch aneurysm and aortic dissection between 1989 and 2003, of whom 58 patients had proximal aortic repair, 62 had distal arch repair, and 62 had total arch repair. We assessed factors associated with the development of vocal cord paralysis and examined in detail the clinical outcome of patients with vocal cord paralysis. RESULTS: Postoperative vocal cord paralysis occurred in 40 patients. Multiple logistic regression analysis revealed the following risk factors with odds ratios (OR) for vocal cord paralysis: extension of procedures into distal arch (OR, 17.0), chronic dilatation of the aorta at the left subclavian artery (OR, 9.14), and total arch repair (OR, 4.24). Adoption of open-style stent-grafts reduced the incidence of vocal cord paralysis (OR, 0.031). The postoperative occurrence of vocal cord paralysis itself emerges as an independent predictor of pulmonary complications (OR, 4.12) and leads to a longer duration of hospital stay. CONCLUSIONS: The risk of vocal cord paralysis after aortic arch surgery depends on surgical factors, such as aneurysmal involvement of the distal arch, or the application of newer, less invasive surgical procedures. Vocal cord paralysis after aortic arch surgery itself, under aggressive postoperative respiratory management, did not increase aspiration pneumonia but was associated with postoperative complications leading to higher hospital mortality and prolonged hospitalization.

[Anesthetic management of two patients with Brugada-type ECG and of different clinical severity].

Brugada syndrome is an arrhythmia syndrome characterized by typical electrocardiogram (Brugada-type ECG) and development of ventricular fibrillation (Vf) without any distinct structural heart diseases. The essential goal in the management of Brugada syndrome is to avoid the development of Vf. However, there has been no established consensus on pre-operative risk assessment of patients with Brugada-type ECG. We recently experienced two cases of anesthetic managements for patients with Brugada-type ECG. Based on these experiences and recent cardiological progress on the risk stratification of Brugada syndrome, we thoroughly discuss on the peri-operative managements for patients with Brugada-type ECG.

Development of colitis in signal transducers and activators of transcription 6-deficient T-cell receptor alpha-deficient mice: a potential role of signal transducers and activators of transcription 6-independent interleukin-4 signaling for the generation of Th2-biased pathological CD4+ betabetaT cells.

Forbidden CD4(+)betabeta T cells, which produce interleukin (IL)-4 predominantly, are a pathological subset in the development of colitis in T-cell receptor alpha chain (TCRalpha)-deficient mice. Stimulation of naive CD4(+) T cells with IL-4 induces Th2 development via the activation of signal transducers and activators of transcription (STAT) 6. In the present study, we had found that IL-4 enhanced the expression of STAT6 in CD4(+)betabeta T cells isolated from TCRalpha(-/-) mice with colitis, suggesting that the IL-4 signal in the CD4(+)betabeta T cells is mediated by STAT6. To further investigate the role of STAT6 in the development of colitis induced by TCRalpha deficiency, we generated double-deficient mice by crossing TCRalpha(-/-) mice and STAT6(-/-) mice. Surprisingly, STAT6 deficiency did not result in decreased severity of colitis in TCRalpha(-/-) mice. STAT6-deficient CD4(+)betabeta T cells produced IL-4 and intraperitoneal injection of anti-IL-4 monoclonal antibody in the nondiseased TCRalpha(-/-) and STAT6 double-deficient mice prevented the colitis formation, thus indicating that the cells differentiated into the Th2 phenotype have the ability to mediate the development of the colitis in the absence of STAT6.