Cytokines In Cancer Patients Research Articles

Аутосенсибилизация при злокачественных новообразованиях

Autoantibody formation, as a physiological mechanism of homeostatic regulation, leads to pathological processes when overexpressed. Autoantibodies are produced when the concentration of autoantigens increases, which occurs as a result of tumour necrotization and metastasizing. Autosensitization in known to develop in chronic inflammatory and tumour processes. It is of interest to clarify the significance of antiinflammatory cytokines for the formation of autoantibodies in malignant neoplasms. The purpose of this article was to identify the link between autoantibody formation and concentrations of anti-inflammatory cytokines in cancer patients. Materials and methods. Immunoassay data of 210 cancer patients of Biokor medical company (Arkhangelsk) were analysed. In the peripheral venous blood, the following were measured: antibodies against phospholipid (IgM, IgG), thyroid peroxidase (anti-TPO) and streptolysin (anti-streptolysin O), anti-double stranded DNA (anti-dsDNA) and anti-ribonucleoprotein (anti-RNP), as well as interleukins (IL) 1β, 4, 6, 10 and 13, and tumour necrosis factor (TNF-α). Results. High frequency of elevated concentrations of anti-dsDNA, antiRNP and anti-streptolysin O in the blood of cancer patients was recorded (51.72, 40.48 and 34.78 %, respectively). Most often, increased levels of anti-dsDNA were found, their mean concentrations being the highest as well. The frequency of elevated concentrations of antiphospholipid antibodies was 11.11 % for IgM and 18.42 % for IgG. Increased anti-TPO levels were observed in 14.29 % of cases. Elevated IL-10, IL-1ß and IL-4 were found in 86.90, 23.81 and 10.81 % of cased, respectively, while IL-6 and IL-13 in 5.71 and 3.85 % of cases, respectively. Mean concentrations of the cytokines under study were within the physiological limits, except for IL-10 and TNF-α, which were increased. Elevated concentrations of autoantibodies were associated with increased blood levels of TNF-α and IL-10. Thus, abnormally high blood concentrations of IL-10, which reduces cellular receptor activity, can indirectly contribute to a decrease in the activity of autoantigen disposal and clearance and prolong autosensitization.

Altered insulin sensitivity and immune function in patients with colorectal cancer

Insulin resistance and chronic inflammation have been reported in patients with cancer. However, many of the underlying mechanisms and associations are yet to be unveiled. We examined both the level of insulin sensitivity and markers of inflammation in patients with colorectal cancer for comparison to controls. Clinical exploratory study of patients with colorectal cancer (n=20) and matched controls (n=10). Insulin sensitivity was quantified using the hyperinsulinemic normoglycemic clamp and blood samples were taken for quantification of several key, both intra- and extracellular, inflammatory markers. We analysed the differences in these parameters between the two groups. Patients exhibited both insulin resistance (M-value, patients median (Mdn) 4.57 interquartile range (IQR) 3.49-5.75; controls Mdn 5.79 (IQR 5.20-6.81), p=0.049), as well as increased plasma levels of the pro-inflammatory cytokines IL-1β (patients Mdn 0.48 (IQR 0.33-0.58); controls Mdn 0.36 (IQR 0.29-0.42), p=0.02) and IL-6 (patients Mdn 3.21 (IQR 2.31-4.93); controls Mdn 2.16 (IQR 1.50-2.65), p=0.02). The latter is present despite an almost two to three fold decrease (p<0.01) in caspase-1 activity, a facilitating enzyme of IL-1β production, within circulating immune cells. Patients with colorectal cancer displayed insulin resistance and higher levels of plasma IL-1β and IL-6, in comparison to matched healthy controls. The finding of a seemingly disconnect between inflammasome (caspase-1) activity and plasma levels of key pro-inflammatory cytokines in cancer patients may suggest that, in parallel to dysregulated immune cells, tumour-driven inflammatory pathways also are in effect.

A Comparative and Comprehensive Review of Antibody Applications in the Treatment of Lung Disease.

Antibodies are a type of protein produced by active B cells in response to antigen stimulation. A series of monoclonal antibodies and neutralizing antibodies have been invented and put into clinical use because of their high therapeutic effect and bright developing insight. Patients with cancer, infectious diseases, and autoimmune diseases can all benefit from antibody therapy. However, the targeting aspects and potential mechanisms for treating these diseases differ. In the treatment of patients with infectious diseases such as COVID-19, neutralizing antibodies have been proposed as reliable vaccines against COVID-19, which target the ACE2 protein by preventing virus entry into somatic cells. Monoclonal antibodies can target immune checkpoints (e.g., PD-L1 and CTLA-4), tyrosine kinase and subsequent signaling pathways (e.g., VEGF), and cytokines in cancer patients (e.g. IL-6 and IL-1β). It is debatable whether there is any connection between the use of antibodies in these diseases. It would be fantastic to discover the related points and explain the burden for the limitation of cross-use of these techniques. In this review, we provided a comprehensive overview of the use of antibodies in the treatment of infectious disease and cancer patients. There are also discussions of their mechanisms and history. In addition, we discussed our future outlook on the use of antibodies.

36P Alterations in tumour-promoting cytokines in cancer patients after SARS-CoV-2 infection

Cytokines, chemokines and growth factors (CCGs) are intricately involved in the progression of both solid and haematological malignancies while altering immune responses important for immunity. So far, the alterations in CCGs in cancer patients as a consequence of exposure to the SARS-CoV-2 virus is not sufficiently known.

Interleukin-6 cytokine: a multifunctional glycoprotein for cancer.

Interleukin 6 is a multifunctional cytokine. Its increased levels have been associated with elevated cancer risk, and also these levels have been found to be a prognostic factor for several cancer types. In addition, increased levels have been found in coronary heart disease, insulin resistant patients, advance stage cancer patients, atopy/asthma and in patients with blood circulating micrometastasis. Additionally several studies with different types of cancers have been performed to identify the correlation between interleukin-6 levels, stage, treatment response and severity of symptoms. The influence of interleukin-6 is performed mainly through the janus kinase-signal transducer and activator of transcription-zinc finger protein 1-2 signaling pathway. As a result, the increased levels of interleukin-6 are responsible for enhanced neo-angiogenesis, inhibition of cancer cell apoptosis and deregulation of the control mechanisms in the microenvironment. In addition, increased levels of inteleukin-6 have been found to increase the production of collagen and a-actin which induce interstitial lung disease. In the current mini review we will present information regarding the interleukin-6 and published results in several cancer studies and finally we will comment in future treatment approaches blocking this cytokine in cancer patients.

Modulation of Cytokines in Cancer Patients by Intravenous Ascorbate Therapy.

BackgroundCytokines play an important role in tumor angiogenesis and inflammation. There is evidence in the literature that high doses of ascorbate can reduce inflammatory cytokine levels in cancer patients. The objective of this study was to investigate the effect of treatment by intravenous vitamin C (IVC) on cytokines and tumor markers.Material/MethodsWith the availability of protein array kits allowing assessment of many cytokines in a single sample, we measured 174 cytokines and additional 54 proteins and tumor markers in 12 cancer patients before and after a series of IVC treatments.ResultsPresented results show for our 12 patients the effect of treatment resulted in normalization of many cytokine levels. Cytokines that were most consistently elevated prior to treatments included M-CSF-R, Leptin, EGF, FGF-6, TNF-α, β, TARC, MCP-1,4, MIP, IL-4, 10, IL-4, and TGF-β. Cytokine levels tended to decrease during the course of treatment. These include mitogens (EGF, Fit-3 ligand, HGF, IGF-1, IL-21R) and chemo-attractants (CTAC, Eotaxin, E-selectin, Lymphotactin, MIP-1, MCP-1, TARC, SDF-1), as well as inflammation and angiogenesis factors (FGF-6, IL-1β, TGF-1).ConclusionsWe are able to show that average z-scores for several inflammatory and angiogenesis promoting cytokines are positive, indicating that they are higher than averages for healthy controls, and that their levels decreased over the course of treatment. In addition, serum concentrations of tumor markers decreased during the time period of IVC treatment and there were reductions in cMyc and Ras, 2 proteins implicated in being upregulated in cancer.

Interleukin 12: still a promising candidate for tumor immunotherapy?

Interleukin 12 (IL-12) seemed to represent the ideal candidate for tumor immunotherapy, due to its ability to activate both innate (NK cells) and adaptive (cytotoxic T lymphocytes) immunities. However, despite encouraging results in animal models, very modest antitumor effects of IL-12 in early clinical trials, often accompanied by unacceptable levels of adverse events, markedly dampened hopes of the successful use of this cytokine in cancer patients. Recently, several clinical studies have been initiated in which IL-12 is applied as an adjuvant in cancer vaccines, in gene therapy including locoregional injections of IL-12 plasmid and in the form of tumor-targeting immunocytokines (IL-12 fused to monoclonal antibodies). The near future will show whether this renewed interest in the use of IL-12 in oncology will result in meaningful therapeutic effects in a select group of cancer patients.

Interleukin-6 Cytokine: A Multifunctional Glycoprotein for Cancer

Interleukin 6 is a multifunctional cytokine. Its increased levels have been associated with elevated cancer risk, and also these levels have been found to be a prognostic factor for several cancer types. In addition, increased levels have been found in coronary heart disease, insulin resistant patients, advance stage cancer patients, atopy/asthma and in patients with blood circulating micrometastasis. Additionally several studies with different types of cancers have been performed to identify the correlation between interleukin-6 levels, stage, treatment response and severity of symptoms. The influence of interleukin-6 is performed mainly through the janus kinase-signal transducer and activator of transcription-zinc finger protein 1-2 signaling pathway. As a result, the increased levels of interleukin-6 are responsible for enhanced neo-angiogenesis, inhibition of cancer cell apoptosis and deregulation of the control mechanisms in the microenvironment. In addition, increased levels of inteleukin-6 have been found to increase the production of collagen and a-actin which induce interstitial lung disease. In the current mini review we will present information regarding the interleukin-6 and published results in several cancer studies and finally we will comment in future treatment approaches blocking this cytokine in cancer patients.

Effect of high-dose intravenous vitamin C on inflammation in cancer patients.

BackgroundAn inflammatory component is present in the microenvironment of most neoplastic tissues. Inflammation and elevated C-reactive protein (CRP) are associated with poor prognosis and decreased survival in many types of cancer.Vitamin C has been suggested as having both a preventative and therapeutic role in a number of pathologies when administered at much higher-than-recommended dietary allowance levels.Since in vitro studies demonstrated inhibition of pro-inflammatory pathways by millimolar concentrations of vitamin C, we decided to analyze the effects of high dose IVC therapy in suppression of inflammation in cancer patients.Methods45 patients with prostate cancer, breast cancer, bladder cancer, pancreatic cancer, lung cancer, thyroid cancer, skin cancer and B-cell lymphoma were treated at the Riordan Clinic by high doses of vitamin C (7.5 g -50 g) after standard treatments by conventional methods.CRP and tumor markers were measured in serum or heparin-plasma as a routine analysis. In addition, serum samples were collected before and after the IVCs for the cytokine kit tests.ResultsAccording to our data positive response to treatment, which was demonstrated by measurements of C- reactive protein, was found in 75% of patients and progression of the inflammation in 25% of patients. IVC treatments on all aggressive stage cancer patients showed the poor response of treatment.There was correlation between tumor markers (PSA, CEA, CA27.29 and CA15-3) and changes in the levels of C-reactive protein.Our test of the effect of IVC on pro-inflammatory cytokines demonstrated that inflammation cytokines IL-1α, IL-2, IL-8, TNF-α, chemokine eotaxin and CRP were reduced significantly after treatments.ConclusionsThe high dose intravenous ascorbic acid therapy affects C-reactive protein levels and pro-inflammation cytokines in cancer patients. In our study, we found that modulation of inflammation by IVC correlated with decreases in tumor marker levels.In summary, our data support the hypothesis that high dose intravenous ascorbate treatments may reduce inflammation in cancer patients. Our results suggest that further investigations into the use of IVC to reduce inflammation in diseases where inflammation is relevant are warranted.

Pathophysiological Role of Hormones and Cytokines in Cancer Cachexia

We investigated the role of fasting hormones and pro-inflammatory cytokines in cancer patients. Hormones (ghrelin, adiponectin, and leptin) and cytokines (TNF-α, IFN-γ, and IL-6) were measured by ELISA or RIA in lung cancer and colorectal cancer patients before the administration of cancer therapy, and measurements were repeated every 2 months for 6 months. From June 2006 to August 2008, 42 patients (19 with colorectal cancer and 23 with lung cancer) were enrolled. In total, 21 patients were included in the cachexia group and the others served as a comparison group. No significant difference in the initial adiponectin, ghrelin, TNF-α, IFN-γ, or IL-6 level was observed between groups, although leptin was significantly lower in cachectic patients than in the comparison group (15.3 ± 19.5 vs 80.9 ± 99.0 pg/mL, P = 0.007). During the follow-up, the patients who showed a > 5% weight gain had higher ghrelin levels after 6 months. Patients exhibiting elevated IL-6 levels typically showed a weight loss > 5% after 6 months. A blunted adiponectin or ghrelin response to weight loss may contribute to cancer cachexia and IL-6 may be responsible for inducing and maintaining cancer cachexia.

Positive affect and inflammation during radiation treatment for breast and prostate cancer

There is growing evidence that positive affect may influence health and immune function, although few studies have examined links between positive affect and immune processes in clinical populations. The purpose of this study was to examine whether positive affect is associated with changes in proinflammatory cytokines in cancer patients undergoing radiation treatment. Subjects were 50 individuals with early-stage breast and prostate cancer who completed psychosocial questionnaires and provided blood samples at seven time points before, during, and after radiation treatment. Positive affect was assessed before treatment onset using the CES-D (Center for Epidemiological Studies Depression Scale). Blood samples were assayed for serum levels of proinflammatory cytokines IL-1β and IL-6. Patients with higher levels of positive affect before treatment exhibited higher mean levels of IL-1β and IL-6 during radiation treatment (all ps < .05). Results suggest that positive affect enhances the acute inflammatory response to radiation treatment, perhaps facilitating tissue repair processes.

Tumor Therapy Applying Membrane-bound Form of Cytokines

Tumor therapy using cytokines has been developed for last two decades. Several recombinant cytokines and tumor cell vaccines produced by cytokine gene transfer have been in clinical trials, but several side effects hamper routine clinical applications. Many cytokines are originally expressed as membrane-bound form and then processed to secretory form exerting paracrine effects. Though functional differences of these two types of cytokines are elusive yet, the membrane-bound form of cytokine may exert its effects on restricted target cells as a juxtacrine, which are in physical contacts. With the efforts to improve antitumor activities of cytokines in cancer patients, developing new strategies to alleviate life-threatening side effects became an inevitable goal of tumor immunologists. Among these, tumor cell vaccines expressing cytokines as membrane-bound form on tumor cell surface have been developed by genetic engineering techniques with the hope of selective stimulation of the target cells that are in cell-to-cell contacts. In this review, recent progress of tumor cell vaccines expressing membrane-bound form of cytokines will be discussed.

Lenalidomide and pomalidomide strongly enhance tumor cell killing in vitro during antibody-dependent cellular cytotoxicity (ADCC) mediated by trastuzumab, cetuximab and rituximab

3023 Background: Potential mechanisms of action of lenalidomide and pomalidomide (CC-4047) include anti-angiogenic, anti- proliferative and immunomodulatory activities, e.g., enhancement of T cell and NK cell function. Both drugs appear to enhance T cell activation and Th1-type cytokines in cancer patients. Also, both drugs have been shown to enhance rituximab-mediated protection in a mouse lymphoma model. Methods: We have utilized an in vitro ADCC system to assess the ability of these drugs to enhance human NK cell function in response to the approved therapeutic antibodies trastuzumab, cetuximab and rituximab. Results: Pre-treatment of NK cells with either pomalidomide or lenalidomide greatly enhanced IFN-γ production by NK cells in response to IgG in the presence of either IL-2 or IL- 12. In a series of functional ADCC assays, Her2/neu overexpressing breast cancer cells (SKBR3 &amp; MCF-7) pre-coated with trastuzumab, EGFR positive colorectal cancer cells (HCT-116) pre-coated with cetuximab and NHL cell lines (Namalwa, Farage &amp; Raji) pre-coated with rituximab, were exposed to NK cells pre-treated with pomalidomide, lenalidomide or thalidomide. Both pomalidomide and lenalidomide synergistically increased (up to 6-fold) NK cell-mediated killing of antibody coated tumor cells in a dose-dependent manner. Thalidomide had no effect in this system. There was minimal tumor cell killing by antibody alone or in the absence of antibody. The presence of IL-2 or IL-12 was required to see enhanced killing by either drug. Enhanced ADCC was associated with increased signaling in NK cells, specifically with inhibition of the negative regulator SHIP-1. Other downstream effects on signaling pathways are also being investigated. Monocyte-mediated tumor cell ADCC was also enhanced by both drugs. Conclusions: We have shown that pomalidomide and lenalidomide (but not thalidomide) strongly enhance the ability of therapeutic antibodies to induce ADCC via NK cell/monocyte-mediated killing of tumor cells in vitro. These results provide a strong rationale for combination of either lenalidomide or pomalidomide with antibodies to tumor-specific surface antigens in cancer patients. No significant financial relationships to disclose.

Elevation of circulating plasma cytokines in cancer patients with high plasma parathyroid hormone-related protein levels.

Parathyroid hormone (PTH) and PTH-related protein/peptide (PTHrP) bind to the same PTH/PTHrP receptor and stimulate osteoblasts to secrete pro-inflammatory cytokines like interleukin (IL)-6. In patients with primary hyperparathyroidism, elevation of plasma levels of tumor necrosis factor (TNF)-alpha and IL-6 was also described. We, therefore, postulated that PTHrP secreted from cancer cells stimulates the secretion of cytokines and causes increases in their blood levels. Blood concentrations of several cytokines (TNF-alpha, IL-1beta, IL-5, IL-6, IL-8, IL-11 and IL-12) in cancer-bearing patients with or without elevation of blood PTHrP were measured by ELISA. The patients with high plasma PTHrP levels (n=29, intact PTHrP: 8.5 +/- 1.4 pmol/l, normal: <1.1) had higher serum type 1 collagen C-telopeptide (ICTP). Twenty of the patients were hypercalcemic. Plasma concentrations of TNF-alpha, IL-6 and IL-8 were significantly increased in patients with high PTHrP, in either the presence or absence of hypercalcemia. The concentrations of TNF-alpha and IL-6 were also significantly correlated with those of PTHrP. Our observations indicate that high plasma levels of PTHrP in cancer-bearing patients contribute not only to the development of hypercalcemia, but also to the development of the syndrome caused by an excess of pro-inflammatory cytokines.

CIRCADIAN RHYTHMS OF BASIC FIBROBLAST GROWTH FACTOR (bFGF), EPIDERMAL GROWTH FACTOR (EGF), INSULIN-LIKE GROWTH FACTOR-1 (IGF-1), INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN-3 (IGFBP-3), CORTISOL, AND MELATONIN IN WOMEN WITH BREAST CANCER

Background: Circadian rhythms in plasma concentrations of many hormones and cytokines determine their effects on target cells. Methods: Circadian variations were studied in cortisol, melatonin, cytokines (basic fibroblast growth factor [bFGF], EGF, insulin-like growth factor-1 [IGF-1]), and a cytokine receptor (insulin-like growth factor binding protein-3 [IGFBP-3]) in the plasma of 28 patients with metastatic breast cancer. All patients followed a diurnal activity pattern. Blood was drawn at 3h intervals during waking hours and once during the night, at 03:00. The plasma levels obtained by enzyme-linked immunoassay (ELISA) or radioimmunoassay (RIA) were evaluated by population mean cosinor (using local midnight as the phase reference and by one-way analysis of variance (ANOVA). Results: Cortisol and melatonin showed a high-amplitude circadian rhythm and a superimposed 12h frequency. bFGF showed a circadian rhythm with an acrophase around 13:00 with a peak-to-trough interval (double amplitude) of 18.2% and a superimposed 12h frequency. EGF showed a circadian rhythm with an acrophase around 14:20, a peak-to-trough interval of 25.8%, and a superimposed 12h frequency. IGF-1 showed a high value in the morning, which is statistically different t test) from the low value at 10:00, but a regular circadian or ultradian rhythm was not recognizable as a group phenomenon. IGFBP-3 showed a low-amplitude (peak-to-trough difference 8.4%) circadian rhythm with the acrophase around 11:00 and low values during the night. Conclusions: (1) Circadian periodicity is maintained in hospitalized patients with metastatic breast cancer. (2) Ultradian (12h) variations were superimposed on the circadian rhythms of the hormones and several of the cytokines measured. (3) Studies of hormones and cytokines in cancer patients have to take their biologic rhythms into consideration. (4) The circadian periodicity of tumor growth stimulating or restraining factors raises questions about circadian and/ or ultradian variations in the pathophysiology of breast cancer. (Chronobiology International, 18(4), 709–727)

Characterization of Intracellular Cytokine Profile of CD4(+) T Cells in Peripheral Blood and Tumor-draining Lymph Nodes of Patients with Gastrointestinal Cancer

Analysis of serum cytokine levels has shown that cancer-bearing hosts have lower levels of IL-2 and IFN-gamma, suggesting that Th1-type immunity is impaired by cancer. However, the mechanisms of the Th1 dysfunction are not clearly understood. The frequencies of Th1 cells in CD4(+) helper T cells were evaluated with an intracytoplasmic cytokine staining method in peripheral blood lymphocytes (PBL) and lymph node lymphocytes (LNL) of patients with gastrointestinal cancer. Activation of lymphocytes with PMA + Ionomycin induced the expression of IL-2 and IFN-gamma in each lymphocyte population. Compared with PBL of non-malignant donors, PBL in cancer patients contained significantly lower frequencies of CD4(+) T cells that produced IL-2 and IFN-gamma. LNL in cancer patients also contained lower levels of IL-2- and IFN-gamma-producing CD4(+) T cells, although the percentages did not show significant differences from those of PBL in the same patients. Our data suggest that suppression of Th1 cytokine in cancer patients is, at least in part, due to the decreased frequency of Th1 cells with CD4(+) phenotype.

Therapeutic potential of melatonin in immunodeficiency states, viral diseases, and cancer.

Maintenance of health depends on the ability to respond appropriately to environmental stressors via reciprocal interactions between the body and the brain. In this context, it is well recognized that the pineal hormone melatonin (MLT) plays an important role. T-helper cells bear G-protein-coupled MLT cell membrane receptors and, perhaps, MLT nuclear receptors. Activation of MLT receptors enhances the release of T-helper cell cytokines, such as gamma-interferon and interleukin-2 (IL-2), as well as activation of novel opioid cytokines which crossreact immunologically with both interleukin-4 and dynorphin B. MLT has been reported also to enhance the production of interleukin-1, interleukin-6 and interleukin-12 in human monocytes. These mediators may counteract secondary immunodeficiencies, protect mice against lethal viral and bacterial diseases, synergize with IL-2 against cancer and influence hematopoiesis. Hematopoiesis is influenced by MLT-induced-opioids (MIO) acting on kappa 1-opioid receptors present on bone marrow macrophages. Clinically, MLT could amplify the anti-tumoral activity of low dose IL-2, induce objective tumor regression, and prolong progression-free time and overall survival. MLT seems to be required for the effectiveness of low dose IL-2 in those neoplasias that are generally resistant to IL-2 alone. Similar findings were obtained in a study in which MLT was combined with gamma-interferon in metastatic renal cell carcinoma. In addition, MLT in combination with low-dose IL-2 was able to neutralize the surgery-induced lymphocytopenia in cancer patients. IL-2 treatment in patients results in activation of the immune system and creates the most suitable biological background for MLT. The finding that MLT stimulates IL-12 production from human monocytes only if incubated in presence of IL-2 further supports this concept. On the other hand, high concentrations of MLT have been found in human breast cancer tissue. The MLT concentration, which was 3 orders of magnitude higher than that present in the plasma, correlated positively with good prognostic markers such as estrogen receptor status and nuclear grade. Whether this relates to the immunoneuroendocrine action of MLT remains to be established. Clinical studies are needed on the effect of MLT in combination with IL-2 or other cytokines in cancer patients and viral diseases including HIV-infected patients.

Nitrite/ nitrate and cytokine levels in bronchoalvelar lavage fluid of lung cancer patients

Cytokines are produced by tumor cells in vitro, but evidence for in vivo increased production of cytokines in cancer patients is controversial. Conversely, nitric oxide (NO) is implicated increasingly in the mediation of cytokine effects. Lung cancer patients may show an increased local production of cytokines and NO, and chronic paracrine exposure of epithelial lung cells to these medicators may influence the production of surfactant phosphatidylcholine. The presence of the cytokine tumor necrosis factor (TNF alpha), interleukin-1 (IL-1), and interleukin-6 (IL-6), as well as NO, cyclic guanosine 3'5' monophosphate (cGMP) and phosphatidylcholine levels in bronchoalveolar lavage fluid (BLF) of lung cancer patients were investigated. Bronchoalveolar lavage fluid was obtained from 30 male smokers: 22 patients with squamous cell lung cancer and 8 subjects without cancer. When compared with the control subjects, the cancer patients had elevated BLF levels of TNF alpha (1.58 +/- 0.47 vs. 0.04 +/- 0.02 pg/microgram protein, P < 0.001), IL-6 (1.39 +/- 0.29 vs. 0.04 +/- 0.02 pg/microgram protein, P < 0.001), and NO2-/NO3- (23.3 +/- 5.6 vs 1.1 +/- 0.6 nmol/mg protein, P < 0.001). However, phosphatidylcholine levels were lower in those with cancer than in the control subjects (3.0 +/- 1.2 vs. 24.8 +/- 6.4 micrograms protein, P < 0.001). The results showed in vivo production of inflammatory cytokines in human lung cancer and increased tumor-associated NO production, as suggested by increased levels of nitrite/nitrate in the BLF. A decreased phosphatidylcholine content in the BLF also was found in patients with lung cancer.