Berran Yucesoy

Diseases caused by silica: mechanisms of injury and disease development

While silica particles are considered to be fibrogenic and carcinogenic agents, the mechanisms responsible are not well understood. This article summarizes literature on silica-induced accelerated silicosis, chronic silicosis, silico-tuberculosis, bronchogenic carcinoma, and immune-mediated diseases. This article also discusses the generation of reactive oxygen species (ROS) that occurs directly from the interaction of silica with aqueous medium and from silica-stimulated cells, the molecular mechanisms of silica-induced lung injuries with focus on silica-induced NF-kappaB activation, including its mechanisms, possible attenuation and relationship to silica-induced generation of cyclooxygenase II and TNF-alpha. Silica-induced AP-1 activation, protooncogene expression, and the role of ROS in these processes are also briefly discussed.

Role of inflammation in chemical-induced hepatotoxicity☆

The liver, which is the major organ responsible for the metabolism of drugs and toxic chemicals, is also the primary target organ for many toxic chemicals. Increasing evidence has indicated that inflammatory processes are intimately involved in chemical-induced hepatotoxic processes, and like other inflammatory diseases, such as autoimmunity, are responsible for producing mediators that can effect liver damage or repair. This review will summarize our current understanding of how inflammatory processes influence hepatic pathology and repair following exposure to established hepatotoxic chemicals including carbon tetrachloride, an industrial chemical, and acetaminophen, a widely used analgesic.

Interleukin-6 Treatment Augments Cutaneous Wound Healing in Immunosuppressed Mice

It has been postulated that the inflammatory response that occurs after cutaneous wounding is a prerequisite for healing and that inflammatory cytokines, such as interleukin-6 (IL-6) are involved in this process. We showed previously that IL-6-deficient mice display delayed wound healing, which could be reversed by administration of a murine IL-6 expression plasmid or recombinant murine IL-6 (rMuIL-6). In the present study, we observed that delayed cutaneous wound healing, which occurs as a result of glucocorticoid-induced immunosuppression, can also be reversed by rMuIL-6, as evidenced by epithelialization, granulation tissue formation, and wound closure. In vehicle control mice, rMuIL-6 did not augment healing but rather delayed the process. Immunochemical studies indicated that the expression of matrix metalloproteinase-10 (MMP-10) was increased in dexamethasone-treated mice and that rMuIL-6 treatment reduced its expression, indicating that IL-6 may influence dermal matrix formation and, specifically, collagen synthesis. These results demonstrate that IL-6 can restore abnormal wound repair that occurs in immunodeficiency and suggest its use as a potential therapy.

Association of interleukin-1 gene polymorphisms with dementia in a community-based sample: the Honolulu-Asia Aging Study.

The interleukin-1 (IL-1) pro-inflammatory cytokine family participates in inflammatory processes and vessel damage involved in neurodegeneration. Recent studies suggest that Alzheimers disease (AD) and vascular dementia (VaD) may share genetic risk factors. In this study, the frequency of polymorphisms in the genes coding for interleukin (IL)-1alpha, IL-1beta and the IL-1 receptor antagonist (RN) and their genotype associations with late-onset AD and VaD were determined in a Japanese-American cohort of men (n=931) participating in the Honolulu-Asia Aging Study (HAAS). A significant association was found between the IL-1beta (-511) and IL-1RN (+2018) polymorphisms and AD, suggesting that these variants confer an increased risk. Possessing the IL-1beta (-511) T/T genotype was also associated with VaD. There was no difference in the IL-1beta (+3953) frequency among the groups. Our results support the hypothesis that certain genetic variations contained within the IL-1 gene family contribute to the pathogenesis of dementia.

Polymorphisms of the IL-1 gene complex in coal miners with silicosis.

BACKGROUND Silicosis is characterized by fibrosing nodular lesions that eventually develop into progressive pulmonary fibrosis. Pro-inflammatory cytokines, such as interleukin-1 (IL-1), play a key role in the development of silicosis by regulating mediators which are responsible for lung injury, inflammation, and potentially fibrosis. To study whether functional single nucleotide polymorphisms (SNPs) located in the regulatory elements of genes coding for the IL-1alpha, IL-1beta, and IL-1 receptor antagonist (RA) cytokines are associated with silicosis, we examined 318 Caucasian cases confirmed histopathologically with pulmonary silicosis and 163 controls without any apparent inflammation or other pulmonary disease. METHODS Genotyping was carried out by polymerase chain reaction-restriction fragment length polymorphism technique. RESULTS The proportion of the IL-1RA (+ 2018) allele 2 genotype was increased in miners with silicosis (0.27) compared to controls (0.16). The odds of being a case were 2.15 (CI = 1.4-3.3) times higher for subjects with at least one copy of allele 2. No statistically significant differences in the allelic frequencies or genotype distributions for IL-1alpha (+ 4845) or IL-1beta (+ 3953) were found between the control and disease groups. CONCLUSIONS This is the first report showing an association between the IL-1RA (+ 2018) polymorphism and silicosis, and suggests that this polymorphism may confer increased risk for the development of the disease.

Cytokine Polymorphisms Play a Role in Susceptibility to Ultraviolet B-Induced Modulation of Immune Responses after Hepatitis B Vaccination

UVB exposure can alter immune responses in experimental animals and humans. In an earlier human volunteer study, we demonstrated that hepatitis B-specific humoral and cellular immunity after vaccination on average were not significantly affected by UVB exposure. However, it is known that individuals differ in their susceptibility to UVB-induced immunomodulation, and it was hypothesized that polymorphisms in specific cytokines may play a role in this susceptibility. In this respect, we previously demonstrated that immune responses after hepatitis B vaccination are influenced by the minor allelic variant of IL-1β in the general population. For all volunteers, single nucleotide polymorphisms were determined for the following UV response-related cytokines: IL-1 receptor antagonist (+2018), IL-1α (+4845), IL-1β (+3953), TNF-α (−308), and TNF-α (−238). Exposure to UVB significantly suppressed Ab responses to hepatitis B in individuals with the minor variant for the IL-1β polymorphism. Increased minimal erythema dose values (just perceptible), which resulted in higher absolute UVB exposures, were observed in the same individuals. There were no associations observed between UVB-induced immunomodulation and the other cytokine polymorphisms examined. This study indicates that individual susceptibility to UVB radiation needs to be considered when studying the effects of UVB in humans.

IL-1beta gene polymorphisms influence hepatitis B vaccination

Considerable variability exists in the vaccine response to hepatitis B with 5-10% of healthy young adults demonstrating no or inadequate responses following a standard vaccination schedule. As the interleukin-1beta (IL-1beta) cytokine has been shown to be important in the development of immune responses, we determined whether vaccine efficacy is influenced by genetic polymorphisms associated with IL-1beta expression. Ninety-two healthy individuals who were negative for antibodies to hepatitis B antigen (anti-HBs) were vaccinated against hepatitis B according to a standardized schedule. At selected times, antibody titers and lymphoproliferative capacity to hepatitis B surface antigen (HBsAg) were determined. DNA genotyping for IL-1beta polymorphisms using a polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) technique demonstrated that both the anti-HBs titer and the T-cell lymphoproliferative response to HBsAg are significantly increased in individuals possessing the IL-1beta (+3953) minor allelic variant.

Diisocyanate asthma and gene-environment interactions with IL4RA, CD-14, and IL-13 genes

BACKGROUND Diisocyanate asthma (DA) affects 2% to 10% of exposed workers, yet the pathogenetic mechanisms underlying this disorder remain ill defined. OBJECTIVE To determine if specific single nucleotide polymorphisms (SNPs) of interleukin 4 receptor alpha (IL4RA), IL-13, and CD14 promoter genes are associated with DA. METHODS Sixty-two workers with DA confirmed by specific inhalation challenge (SIC) and 75 diisocyanate-exposed, SIC-negative workers were analyzed for SNPs associated with IL4RA, IL-13, and CD14 promoter genes. RESULTS No associations were found with individual SNPs and DA. When stratified according to specific diisocyanate exposure, a significant association was found between IL4RA (I50V) II and DA among individuals exposed to hexamethylene diisocyanate (HDI) (odds ratio [OR], 3.29; 95% confidence interval [CI], 1.33-8.14; P = .01) only. Similarly, the IL4RA (I50V) II and IL-13 (R110Q) RR combination was significantly associated with DA in HDI-exposed workers (OR, 4.13; 95% CI, 1.35-12.68; P = .01), as was the IL4RA (I50V) II and CD14 (C159T) CT genotype combination (OR, 5.2; 95% CI, 1.82-14.88; P = .002) and the triple genotype combination IL4RA (I50V) II, IL-13 (R110Q) RR, and CD14 (C159T) CT (OR, 6.4; 95% CI, 1.57-26.12; P = .01). CONCLUSIONS Gene-environmental interactions may contribute to the pathogenesis of DA, and gene-gene interactions may modulate this relationship.

Inhalation of Toluene Diisocyanate Vapor Induces Allergic Rhinitis in Mice

Diisocyanates are the leading cause of occupational asthma, and epidemiological evidence suggests that occupational rhinitis is a comorbid and preceding condition in patients who develop asthma. The goal of the present studies was to develop and characterize a murine model of toluene diisocyanate (TDI)-induced rhinitis. Female C57BL/6 mice were exposed to workplace-relevant concentrations of TDI vapor via inhalation for 4 h/day for 12 days with or without a 2-wk rest period and TDI challenge. Mice exposed 12 consecutive weekdays to 50 parts per billion TDI vapor showed elevated total serum IgE and increased TDI-specific IgG titers. Breathing rates were decreased corresponding with increased inspiratory time. TDI exposure elevated IL-4, IL-5, IL-13, and IFN-γ mRNA expression in the nasal mucosa, suggesting a mixed Th1/Th2 immune response. Expressions of mRNA for proinflammatory cytokines and adhesion molecules were also up-regulated. These cytokine changes corresponded with a marked influx of inflammatory cells into the nasal mucosa, eosinophils being the predominant cell type. Removal from exposure for 2 wk resulted in reduced Ab production, cytokine mRNA expression, and cellular inflammation. Subsequent challenge with 50 parts per billion TDI vapor resulted in robust up-regulation of Ab production, cytokine gene expression, as well as eosinophilic inflammation in the nasal mucosa. There were no associated changes in the lung. The present model shows that TDI inhalation induces immune-mediated allergic rhinitis, displaying the major features observed in human disease. Future studies will use this model to define disease mechanisms and examine the temporal/dose relationship between TDI-induced rhinitis and asthma.

Effects of occupational lead and cadmium exposure on some immunoregulatory cytokine levels in man

The levels of serum interleukin-1beta (IL-1beta), interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-alpha) and gamma-interferon (gamma-IFN) were assessed in the workers who were occupationally exposed to lead and cadmium. The values were compared with the age-matched control group. Blood lead and cadmium levels were significantly raised. Our findings suggest that chronic lead and cadmium exposure in humans resulted in significant suppression of the serum IL-1beta level, but did not alter IL-2 and TNF-alpha levels. The gamma-IFN level was also reduced in lead workers. In contrast, a significant enhancement was observed in the cadmium-exposed group. We conclude from these results that lead and cadmium exposure at chronically high level may affect some cytokine levels in humans.