Understanding Of Inflammatory Processes Research Articles

Pathogenesis of Inflammation in Skin Disease: From Molecular Mechanisms to Pathology.

Many skin diseases begin with inflammatory changes on a molecular level. To develop a more thorough understanding of skin pathology and to identify new targets for therapeutic advancements, molecular mechanisms of inflammation in the context of skin disease should be studied. Current research efforts to better understand skin disease have focused on examining the role of molecular processes at several stages of the inflammatory response such as the dysregulation of innate immunity sensors, disruption of both transcriptional and post-transcriptional regulation, and crosstalk between immune and neuronal processes (neuro-immune crosstalk). This review seeks to summarize recent developments in our understanding of inflammatory processes in skin disease and to highlight opportunities for therapeutic advancements. With a focus on publications within the past 5 years (2019-2024), the databases PubMed and EBSCOhost were used to search for peer-reviewed papers regarding inflammatory molecular mechanisms and skin disease. Several themes of research interest regarding inflammatory processes in skin disease were determined through extensive review and were included based on their relative representation in current research and their focus on therapeutic potential. Several skin diseases such as psoriasis, atopic dermatitis, hidradenitis suppurativa, and scleroderma were described in the paper to demonstrate the widespread influence of inflammation in skin disease.

Persistent Desmoglein-1 downregulation and Periostin accumulation in histologic remission of Eosinophilic Esophagitis

BackgroundPatients with Eosinophilic esophagitis (EoE) require long-lasting resolution of inflammation to prevent fibrostenosis and dysphagia. However, the dissociation between symptoms and histologic improvement suggests persistent molecular drivers despite histologic remission. ObjectiveTo characterize persisting molecular alterations in pediatric patients with EoE using tissue transcriptomics and proteomics. MethodsEsophageal biopsies (n=247) collected prospectively during 189 endoscopies from pediatric patients with EoE (N=36, up to 11 follow-up endoscopies) and pediatric controls (N=44, single endoscopies) were subjected to bulk transcriptomics (n=96) and proteomics (n=151). Intercellular junctions (Desmoglein-1/-3, Desmoplakin, E-cadherin) and epithelial-to-mesenchymal transition (EMT, Vimentin:E-cadherin ratio) were assessed by immunofluorescence staining. ResultsActive EoE (≥15 eosinophils/hpf), inactive EoE (<15 eosinophils/hpf) and deep remission EoE (0 eosinophils/hpf) were diagnosed in 107/185, 78/185 and 41/185 biopsies, respectively. Among the dysregulated genes (up-/downregulated 310/112) and proteins (up-/downregulated 68/16) between active EoE and controls, 17 genes and 6 proteins remained dysregulated in inactive EoE. Using persistently upregulated genes (n=9) and proteins (n=3) only, such as ALOX15, CXCL1, CXCL6, CTSG, CDH26, PRRX1, CLC, EPX, and POSTN was sufficient to separate inactive EoE, as well as deep remission biopsies from control tissue. While 32 differentially expressed genes persisted in deep remission of EoE compared to controls, the proteome normalized except for persistently upregulated Periostin (POSTN). Epithelial-mesenchymal transition normalized in inactive EoE, whereas desmosome recovery remained impaired due to Desmoglein-1 downregulation. ConclusionThe analysis of molecular changes shows persistent EoE-associated esophageal dysregulation despite histologic remission. These data expand our understanding of inflammatory processes and possible mechanisms that underlie tissue remodeling in EoE.

The association of astrogliosis and microglial activation with aging and Alzheimer's disease pathology in the chimpanzee brain.

Aging and neurodegenerative disorders, such as Alzheimer's disease (AD), trigger an immune response known as glial activation in the brain. Recent evidence indicates species differences in inflammatory responses to AD pathology, highlighting the need for additional comparative studies to further understand human-specific neuropathologies. In the present study, we report on the occurrence of astrogliosis, microglial activation, and their relationship with age and AD-like pathology in a cohort of male and female chimpanzees (Pan troglodytes). Chimpanzees with severe astrogliosis exhibited widespread upregulation of hypertrophic astrocytes immunoreactive for glial fibrillary acidic protein (GFAP) throughout all layers of the dorsolateral prefrontal cortex and a loss of the interlaminar palisade. In addition, extreme astrogliosis was associated with increased astrocyte density in the absence of significant microglial activation and AD lesions. A shift from decreased resting to increased phagocytotic microglia occurred with aging, although proliferation was absent and no changes in astrogliosis was observed. Vascular amyloid correlated with decreased astrocyte and microglia densities, while tau lesions were associated with morphological changes in microglia and greater total glia density and glia: neuron ratio. These results further our understanding of inflammatory processes within the chimpanzee brain and provide comparative data to improve our understanding of human aging and neuropathological processes.

Serum Calprotectin Is a Valid Biomarker in Distinction of Bacterial Urinary Tract Infection From Viral Respiratory Illness in Children Under 3 Years of Age.

BackgroundFebrile illnesses in young children can be a major diagnostic challenge, despite the routine use of various laboratory markers. Recent advancements in the understanding of inflammatory processes have highlighted the role of calprotectin, a heterodimer consisting of S100A8 and S100A9 proteins, with many studies suggesting its clinical value as a biomarker of inflammation. This research aimed to evaluate the usefulness of serum calprotectin (sCal) as a biomarker of urinary tract infection (UTI), which was due to its high pooled prevalence and feasibility of urine culture as a diagnostic reference standard selected for a model of bacterial infection in children.MethodsFebrile children aged 0–36 months with suspected UTI based on positive urinalysis or viral respiratory tract infection were included. Children with significant bacteriuria in urine culture were labeled as cases (n = 58), while those with confirmed viral infection (n = 51), as well as those with suspected UTI but sterile urine culture who went on to develop symptoms consistent with viral respiratory infection (n = 7), were labeled as controls. sCal levels were determined by a commercial immunoassay. Conventional inflammation markers (C-reactive protein, procalcitonin, white blood cell count, absolute neutrophil count, and neutrophil percentage) were measured on the day of the clinical examination. Differences in measured inflammatory markers between cases and controls were analyzed with Mann-Whitney U-test. ROC analysis reported cut-off values with the best sensitivity and specificity to distinguish bacterial UTI from viral respiratory infection.ResultsAll analyzed inflammatory biomarkers, including sCal, were significantly higher in cases than in controls. Median concentration of sCal was 4.97 μg/mL (IQR 3.43–6.42) and 2.45 μg/mL (IQR 1.63–3.85) for cases and controls, respectively (p < 0.001). For identifying bacterial UTI, sensitivity and specificity of sCal were 77.6 and 69.0%, respectively, at an adjusted cut-off point of >3.24 μg/mL (AUC 80.2%).ConclusionsCal could have substantial added value in the management of a child with fever and positive urinalysis and is a promising biomarker in distinction between bacterial UTI and viral respiratory causes of febrile illness in children under the age of 3 years.

Hypocrates is a genetically encoded fluorescent biosensor for (pseudo)hypohalous acids and their derivatives

The lack of tools to monitor the dynamics of (pseudo)hypohalous acids in live cells and tissues hinders a better understanding of inflammatory processes. Here we present a fluorescent genetically encoded biosensor, Hypocrates, for the visualization of (pseudo)hypohalous acids and their derivatives. Hypocrates consists of a circularly permuted yellow fluorescent protein integrated into the structure of the transcription repressor NemR from Escherichia coli. We show that Hypocrates is ratiometric, reversible, and responds to its analytes in the 106 M−1s−1 range. Solving the Hypocrates X-ray structure provided insights into its sensing mechanism, allowing determination of the spatial organization in this circularly permuted fluorescent protein-based redox probe. We exemplify its applicability by imaging hypohalous stress in bacteria phagocytosed by primary neutrophils. Finally, we demonstrate that Hypocrates can be utilized in combination with HyPerRed for the simultaneous visualization of (pseudo)hypohalous acids and hydrogen peroxide dynamics in a zebrafish tail fin injury model.

Hyperpolarized 13 C magnetic resonance imaging for noninvasive assessment of tissue inflammation.

Inflammation is a central mechanism underlying numerous diseases and incorporates multiple known and potential future therapeutic targets. However, progress in developing novel immunomodulatory therapies has been slowed by a need for improvement in noninvasive biomarkers to accurately monitor the initiation, development and resolution of immune responses as well as their response to therapies. Hyperpolarized magnetic resonance imaging (MRI) is an emerging molecular imaging technique with the potential to assess immune cell responses by exploiting characteristic metabolic reprogramming in activated immune cells to support their function. Using specific metabolic tracers, hyperpolarized MRI can be used to produce detailed images of tissues producing lactate, a key metabolic signature in activated immune cells. This method has the potential to further our understanding of inflammatory processes across different diseases in human subjects as well as in preclinical models. This review discusses the application of hyperpolarized MRI to the imaging of inflammation, as well as the progress made towards the clinical translation of this emerging technique.

354 ASAS-EAAP Talk: The subclinical non-aureus staphylococcal mastitis in dairy cows: a lipidomics approach

Abstract This study aims to determine the untargeted lipidome of cow milk during non-staphylococcal sub-clinical mastitis. Dairy cow mastitis severely impacts the dairy industry by reducing milk yield and quality and increasing culling rate. Among the pathogens that cause bovine sub-clinical mastitis, non-aureus staphylococci (NAS) have become the most frequently isolated bacteria from milk samples. The molecular mechanisms regulating the mammary gland inflammatory responses to NAS are unclear. Although the application of system biology approaches to mastitis has provided pivotal information by investigating the transcriptome, proteome, and metabolome, the milk lipidome remains undisclosed. We determined the lipidome of 17 dairy cows with NAS sub-clinical mastitis (SM) and we compared the results with the lipidome of the milk of 13 healthy cows. The study was carried out following a liquid chromatography–quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) approach. Sixteen subclasses of lipids were identified in both groups of animals. From 2,506 measured lipids, 631 were significantly changed more than 10 folds (FDR &amp;lt; 0.01 in milk from cows with mastitis as compared to healthy cows. Our results point out the significant influence of NAS on the milk lipidome, contribute to the understanding of inflammatory processes in the bovine udder, and highlight potential novel biomarkers for improving mastitis diagnosis. Part of this work was carried out in “OMICs”, an advanced mass spectrometry platform established by the Università degli Studi di Milano.

MiR-21 binding site SNP within ITGAM associated with psoriasis susceptibility in women.

BackgroundGreat progress has been made in the understanding of inflammatory processes in psoriasis. However, clarifying the role of genetic variability in processes regulating inflammation, including post-transcriptional regulation by microRNA (miRNA), remains a challenge.ObjectivesWe therefore investigated single nucleotide polymorphisms (SNPs) with a predicted change in the miRNA/mRNA interaction of genes involved in the psoriasis inflammatory processes.MethodsStudied SNPs rs2910164 C/G–miR-146a, rs4597342 T/C–ITGAM, rs1368439 G/T–IL12B, rs1468488 C/T–IL17RA were selected using a bioinformatics analysis of psoriasis inflammation-associated genes. These SNPs were then genotyped using a large cohort of women with psoriasis (n = 241) and healthy controls (n = 516).ResultsNo significant association with psoriasis was observed for rs2910164, rs1368439, and rs1468488 genotypes. However, the major allele T of rs4597342 –ITGAM was associated with approximately 28% higher risk for psoriasis in comparison to the patients with the C allele (OR = 1.28, 95% CI 1.01–1.61, p = 0.037). In case of genotypes, the effect of the T allele indicates the dominant model of disease penetrance as the CT and TT genotypes increase the chance of psoriasis up to 42% in comparison to CC homozygotes of rs4597342 (OR = 1.42, 95% CI = 1.05–1.94, p = 0.025).ConclusionSNP rs4597342 in 3'UTR of ITGAM influencing miR-21 binding may be considered a risk factor for psoriasis development. Upregulated miR-21 in psoriasis is likely to inhibit CD11b production in the case of the rs4597342 T allele which may lead to Mac-1 dysfunction, resulting in an aberrant function of innate immune cells and leading to the production of cytokines involved in psoriasis pathogenesis.

Fluorescence-Based Tool To Detect Endogenous Peroxynitrite in M1-Polarized Murine J774.2 Macrophages.

Oxidative stress and inflammation are intrinsically linked to each other. In addition, they are implicated in the evolution and progression of noncommunicable diseases (NCDs). Large amounts of reactive oxygen species (ROS) are generated as part of the immune response toward NCDs. Among all of the ROS species, peroxynitrite (ONOO-) has the shortest half-life with <20 ms under typical physiological conditions. Hence, detecting ONOO- and studying its generation in vitro allows for a better understanding of inflammatory processes. We demonstrate that peroxyresorufin-1 (PR1) is a selective and sensitive ONOO- fluorescence-based sensor in J774.2 macrophages. PR1 was able to detect changes in ONOO- production upon investigation of different factors: enhanced generation of ONOO- through LPS and IFN-γ as well as diminished ONOO- production with the introduction of superoxide scavengers and nitric oxide synthase inhibitors. Our study validates PR1 as an effective tool for the detection of ONOO- in J774.2 murine macrophages and should allow for further elucidation of ROS biology and chemistry.

Endophenotype Network Models: Common Core of Complex Diseases.

Historically, human diseases have been differentiated and categorized based on the organ system in which they primarily manifest. Recently, an alternative view is emerging that emphasizes that different diseases often have common underlying mechanisms and shared intermediate pathophenotypes, or endo(pheno)types. Within this framework, a specific disease’s expression is a consequence of the interplay between the relevant endophenotypes and their local, organ-based environment. Important examples of such endophenotypes are inflammation, fibrosis, and thrombosis and their essential roles in many developing diseases. In this study, we construct endophenotype network models and explore their relation to different diseases in general and to cardiovascular diseases in particular. We identify the local neighborhoods (module) within the interconnected map of molecular components, i.e., the subnetworks of the human interactome that represent the inflammasome, thrombosome, and fibrosome. We find that these neighborhoods are highly overlapping and significantly enriched with disease-associated genes. In particular they are also enriched with differentially expressed genes linked to cardiovascular disease (risk). Finally, using proteomic data, we explore how macrophage activation contributes to our understanding of inflammatory processes and responses. The results of our analysis show that inflammatory responses initiate from within the cross-talk of the three identified endophenotypic modules.

Macrophages and immune cells in atherosclerosis: recent advances and novel concepts.

Atherosclerotic lesion-related thrombosis is the major cause of myocardial infarction and stroke, which together constitute the leading cause of mortality worldwide. The inflammatory response is considered as a predominant driving force in atherosclerotic plaque formation, growth and progression towards instability and rupture. Notably, accumulation of macrophages in the intima and emergence of a pro-inflammatory milieu are a characteristic feature of plaque progression, and these processes can be modulated by adaptive immune responses. Recently, novel evidences of onsite proliferation of macrophages in lesions and transdifferentiation of smooth muscle cells to macrophages have challenged the prevalent paradigm that macrophage accumulation mostly relies on recruitment of circulating monocytes to plaques. Furthermore, previously unrecognized roles of inflammatory cell subsets such as plasmacytoid dendritic cells, innate response activator B cells or CD8(+) T cells in atherosclerosis have emerged, as well as novel mechanisms by which regulatory T cells or natural killer T cells contribute to lesion formation. Here, we review and discuss these recent advances in our understanding of inflammatory processes in atherosclerosis.

Inflammation of the Dental Pulp

Inflammation of the Dental Pulp

P-172 Despite an Overall Inflammatory Phenotype, IBD Patient Plasma Drives a Regulatory Signature in a Novel Transcriptional Bioassay

Significant advances have been made in the understanding of the role of genetics and environmental factors involved in the pathogenesis of inflammatory bowel disease (IBD). But little is understood how these factors influence the immune system to collectively shape the inflammatory state. Factors such as chemokines, cytokines, and inflammatory lipids act as communicators for immune cells and are key elements in IBD pathogenesis. There is significant literature describing cytokine levels in IBD. These studies have yielded inconsistent results. The complex milieu of inflammatory mediators associated with autoimmune and chronic inflammatory diseases is often too dilute to directly measure in the periphery. Moreover cytokines and cytokines do not act in isolation. The disease phenotype is, in part, a consequence of the combinatorial effect of the many mediators produced by inflammatory and non-inflammatory cells. Our approach relies on the sensitivity of a well-controlled healthy peripheral blood mononuclear cell (PBMC) population to transcriptionally respond to mediators in patient serum or plasma during a co-culture. This response is comprehensively measured with a microarray. The purpose of this study is to evaluate the ability of this method in advancing our understanding of inflammatory processes in IBD. Serum was obtained from treatment-naive Crohn's disease (CD) and ulcerative colitis (UC) patients at Children's Hospital of Wisconsin. For controls, we obtained serum from unrelated healthy volunteers lacking a family history of autoimmune disease. We co-cultured highly characterized healthy control PBMC with patient or control serum. The transcriptional responses to the various mediators in the serum were measured using an Affymetrix GeneChip human genome U133 plus 2.0. Genes were considered differentially expressed if they met the following criteria- FDR < 1%, Fold change >1.4, ANOVA P < 0.05. Ontological analysis was performed using the DAVID annotation tool (http://david.abcc.ncifcrf.gov/). We included 37 IBD (22 CD & 15 UC) patients and 5 controls. We identified total of 1,224 genes that are differentially expressed between patient versus control serum. Of these 656 genes were common to both UC and CD; 329 were unique to CD and 239 were unique to UC. Of these 75% (919/1224) were down-regulated by patient compared to control serum. Top most (>10 fold) genes down-regulated by IBD patients serum compared to controls were IL-1α, IL-6, Gap junction protein β2, CXCL-3, IL-1β, IL-8, integrin β8 and TNF alpha-induced protein 6. Significantly regulated biologic pathways were related to cytokine-cytokine receptor interaction and included, NOD-like receptor signaling, TLR signaling, apoptosis and Jak-STAT signaling pathways. The Ingenuity Pathway Analysis identified IL-10 and TGFβ as significant upstream regulators. IBD patient serum induces distinct signature compared to healthy controls. Serum signature induced by CD patients differs from those induced by UC patient's serum. Despite possessing an overall inflammatory phenotype, the sera of IBD patients contains factors that predominantly suppress pro-inflammatory pathways in healthy cells. This result may indicate that IBD patients' inflammatory cells are inherently unresponsive to regulatory signals in vivo.

0094. Monocyte tace activity profile during sepsis and systemic inflammatory response syndrome

To date, immune-modulatory treatments in sepsis have proved unsuccessful. Better understanding of inflammatory processes might help tailor such therapies more effectively and improve their efficacy. It is now recognised that some patients may require immune stimulating therapies. Monocytes display altered behaviour in response to systemic inflammation; this has been called “deactivation” and is characterised by reduced HLA-DR expression and attenuated tumour necrosis factor-α (TNF) release in response to lipopolysaccharide (LPS) stimulus1. TNF converting enzyme (TACE), activated via p38-mitogen activated protein kinase (MAPK) mediated pathway2, is essential for the shedding of TNF and TNF receptors (TNFRs)-1&2. Altered TACE behaviour may be mechanistically important in deactivation.

C5L2 and C5aR interaction in adipocytes and macrophages: Insights into adipoimmunology

Obesity is associated with inflammation characterized by increased infiltration of macrophages into adipose tissue. C5aR-like receptor 2 (C5L2) has been identified as a receptor for acylation-stimulating protein (ASP) and the inflammatory factor C5a, which also binds C5aR. The present study examines the effects of ligands ASP and C5a on interactions between the receptors C5L2 and C5aR in 3T3-L1 adipocytes and J774 macrophages.BRET experiments indicate that C5L2 and C5aR form homo- and heterodimers in transfected HEK 293 cells, which were stable in the presence of ligand. Cell surface receptor levels of C5L2 and C5aR increased during 3T3-L1 adipocyte differentiation; both receptors are also highly expressed in J774 macrophages. Using confocal microscopy to evaluate endogenous receptors in adipocytes following stimulation with ASP or C5a, C5L2 is internalized with increasing perinuclear colocalization with C5aR. There is little C5a-dependent colocalization in macrophages. While adipocyte-conditioned medium (ACM) increased C5L2–C5aR colocalization in macrophages, this was blocked by C5a. ASP stimulation increased Akt (Ser473) phosphorylation in both cell types; C5a induced slight Akt phosphorylation in adipocytes with less effect in macrophages. ASP, but not C5a, increased fatty acid uptake/esterification in adipocytes.C5L2–C5aR homodimerization versus heterodimerization may thus contribute to differential responses obtained following ASP vs C5a stimulation of adipocytes and macrophages, providing new insights into the complex interaction between these two cell types within adipose tissue. Studying the mechanisms involved in the differential responses of C5L2–C5aR activation based on cell type will further our understanding of inflammatory processes in obesity.

Oxidized phospholipids: emerging lipid mediators in pathophysiology

Oxidized phospholipids are biologically active agents that are generated by lipid peroxidation. They are associated with inflammation, oxidative stress and several diseased states as described by an increasing number of reports. In addition, information about the interaction partners, the binding sites, the intracellular signalling and the metabolizing enzymes of these compounds is rapidly increasing. This review will briefly summarize recent findings and focus on mechanisms with potential pathophysiological relevance. Reports reviewed here provide interesting insights into the involvement of oxidized phospholipids in interleukin transcription, phenotype switching of smooth muscle cells and apoptotic mechanisms of the modified phospholipids as well as the identification of metabolizing enzymes. Recent studies shed some light on oxidized phospholipid-induced signalling with regard to apoptosis, gene expression and receptor-mediated events. They support the notion that the bioactivities of these natural agents detrimentally contribute to the pathological alteration of basic mechanisms to states recognized in numerous medical conditions. Advances in the knowledge of signalling pathways and interaction partners of oxidized phospholipids will increase our understanding of inflammatory processes and molecular mechanisms of various diseases including atherosclerosis and may play an important role in the development of future therapeutic options or diagnostics.

Inflammation Imaging

Acute and chronic lung diseases are almost invariably associated with some degree of inflammation. Cells that evolved as an effective mechanism to counter infection and heal lung tissue may, in some circumstances, themselves be partially responsible for the pathogenesis of chronic lung disease that leads to irreversible lung damage and loss of lung function. Although standard measurements of lung function can document the progression of disease, the contributions of the numerous interacting elements to the process are difficult to measure in life. The use of molecular imaging techniques allows the different components of the inflammatory response to be monitored in situ in humans. In particular, positron emission tomography of selected markers targeted to specific cells and biochemical pathways can provide accurate measurements of disease activity, enabling a better understanding of inflammatory processes at all stages of disease. The practicability of sequential measurements allows one to monitor the natural history of different lung diseases. More importantly, imaging provides a unique tool for quantification of the modulation of discrete and specific aspects of inflammatory lung disease by targeted interventions. This should facilitate the development of new treatment strategies with better specificity for key elements of each disease.

Transcriptional up-regulation of the signaling regulatory protein LNK in activated endothelial cells1

A better understanding of inflammatory processes in endothelial cells (ECs) might reveal new ways of controlling inflammation and graft rejection. This study investigates EC genes regulated in response to human tumor necrosis factor (TNF)-alpha and xenogeneic natural antibodies (XNAs) that contribute to endothelial activation during transplantation. Gene expression between resting and activated ECs was investigated by RNA differential display reverse-transcriptase polymerase chain reaction and confirmed by reverse-Northern blot. Forty-five cDNA fragments corresponding to genes up-regulated in activated ECs were identified. Our findings show that TNF-alpha-mediated EC activation was associated with increased levels of mRNA for the adaptor protein Lnk, the nuclear protein RED, and the initiation factor eIF4G. We further show that Lnk and eIF4G were also up-regulated in response to XNA binding to ECs. Our data suggest that TNF-alpha and XNAs could share common signaling pathways involving Lnk and eIF4G but may also drive specific transcriptional events.

Lessons from interleukin-deficient mice: the interleukin-1 system.

The study of cytokine-deficient mice has provided important information for a better understanding of inflammatory processes. In this report, the characterization of mice deficient for various components of the interleukin (IL)-1 system is reviewed. Results obtained by studying mice deficient for IL-1alpha, IL-1beta, IL-1 receptor antagonist, IL-1 receptor type I, IL-1 receptor accessory protein, IL-1 receptor-associated kinase, and the IL-1beta-converting enzyme caspase-1 are summarized. Because some of the components of the IL-1 system are shared with IL-18, similarities between IL-1beta and IL-18 are also discussed.

Activation and regulation of Hsp32 and Hsp70.

Endothelial cells (EC) play a key role in the propagation of inflammatory responses. Better understanding of inflammatory processes in EC might provide new ways of controlling inflammation. We report here that the known antioxidant pyrrolidinedithiocarbamate (PDTC) leads to time and dose dependent activation of heat-shock protein 70 (Hsp70) as well as Hsp32 in EC. We further demonstrate that PDTC activates heat-shock factor 1 (HSF1), one of several transcription factor involved in the upregulation of heat-shock proteins. And more importantly, we demonstrate that Hsp32 as well as Hsp70 can be upregulated independently of the transcription factor nuclear factor kappaB (NF-kappaB). The presented data provide further insight into the mechanism of Hsp32 and Hsp70 regulation, as well as further distinguishing these genes from other so called 'protective genes' whose upregulation depends on the activation of NF-kappaB. These findings indicate that Hsp32 and Hsp70 might be ideal candidates among protective genes. Hsp32 and Hsp70 provide many desirable protective effects but, being independent of NF-kappaB, would leave open the option to interfere with the upregulation of proinflammatory genes by modulating the activation of NF-kappaB.