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Allergology International : Official... Sep 2010Amphiregulin (AR) is expressed in Th2 cells, rather than Th1 cells, and plays an important role in Th2 cell/cytokine-mediated host defense against nematodes. We also...
BACKGROUND
Amphiregulin (AR) is expressed in Th2 cells, rather than Th1 cells, and plays an important role in Th2 cell/cytokine-mediated host defense against nematodes. We also found earlier that AR mRNA expression was strongly upregulated in inflamed tissue during Th2 cell/cytokine-mediated fluorescein isothiocyanate (FITC)-induced contact hypersensitivity (CHS), suggesting a contribution of AR to the induction of those responses.
METHODS
To elucidate the role of AR in the induction of FITC- or dinitrofluorobenzene (DNFB)-induced CHS, AR-deficient mice were sensitized and/or challenged with FITC or DNFB epicutaneously. The levels of FITC-mediated skin dendritic cell (DC) migration and FITC-specific lymph node cell proliferation and cytokine production were assessed by flow cytometry, [3H]-thymidine incorporation and ELISA, respectively, after FITC sensitization. The degree of ear swelling, the activities of myeloperoxidase (MPO) and eosinophil peroxidase (EPO) in inflammatory sites and the levels of FITC-specific immunoglobulin (Ig) in sera were determined by histological analysis, colorimetric assay and ELISA, respectively, after FITC challenge.
RESULTS
DC migration and FITC-specific lymph node cell proliferation and cytokine production were normal in the AR-deficient mice. Ear swelling, tissue MPO and EPO activities and FITC-specific serum Ig levels were also similar in AR-deficient and -sufficient mice.
CONCLUSIONS
Amphiregulin is not essential for the induction of FITC- or DNFB-induced CHS responses in mice.
Topics: Amphiregulin; Animals; Cell Movement; Cell Proliferation; Cytokines; Dendritic Cells; Dermatitis, Contact; Dinitrofluorobenzene; EGF Family of Proteins; Eosinophil Peroxidase; Glycoproteins; Immunoglobulins; Intercellular Signaling Peptides and Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Peroxidase; Th2 Cells
PubMed: 20567134
DOI: 10.2332/allergolint.09-OA-0149 -
Frontiers in Physiology 2022Atopic dermatitis (AD) is a chronic inflammatory skin disease with a high prevalence worldwide. Increasing evidence suggests that the gut microbiota plays an important...
Atopic dermatitis (AD) is a chronic inflammatory skin disease with a high prevalence worldwide. Increasing evidence suggests that the gut microbiota plays an important role in the pathogenesis of AD. In this study, we sought to verify the effect of polysaccharides (DCP) on AD induced by 2,4-Dinitrofluorobenzene (DNFB) in Balb/c mice regarding its impact on the intestinal microbiome. We found that 2-week oral administration of DCP improved AD-like symptoms and histological damage of skin, reduced mast cell infiltration, down-regulated the level of serum total IgE and the expression of pro-inflammatory cytokines such as TNF-α, IFN-γ, IL-4 and IL-6, and increased the expression level of anti-inflammatory cytokine IL-10. The beneficial effect of DCP was attributed to the restoration of the intestinal microbiome composition and the unbalance of the intestinal homeostasis. Our results indicated that DCP might be used as a promising novel microbiota-modulating agent for the treatment of AD.
PubMed: 36160845
DOI: 10.3389/fphys.2022.976421 -
Biochemical Pharmacology Sep 2018The use of immunomodulatory antibiotics to simultaneously target different factors involved in intestinal inflammatory conditions is an interesting but understudied...
OBJECTIVE
The use of immunomodulatory antibiotics to simultaneously target different factors involved in intestinal inflammatory conditions is an interesting but understudied pharmacological strategy. A great therapeutic potential has been obtained with minocycline and doxycycline in experimental colitis. Therefore, understanding the contribution of the different activities of immunomodulatory tetracyclines is crucial for the improvement and translation of their use into clinic.
DESIGN
A comparative pharmacological study including tetracyclines and other antibiotic or immunomodulatory drugs was performed in 2,4-dinitrobenzene sulfonic acid (DNBS)-induced colitis in mice. The correlation between the therapeutic efficacy of each drug and changes in the gut microbiota composition, markers of barrier integrity, inflammatory mediators, microRNAs and TLRs was analysed to identify the main mechanisms of action.
RESULTS
Tetracyclines counteracted most of the markers found altered in DNBS-colitis, which differed from effects of corticosteroid treatment. Of note, administration of tetracyclines led to increased mucosal protection, associated with up-regulated expression of CCL2, miR-142 and miR-375. All drugs with antibiotic activity ameliorated the progression of inflammation and reduced neutrophil-related genes, such as miR-223, despite their effects were not associated with restored intestinal dysbiosis. However, reduced bacterial richness was correlated with increased expression of TLR2 and TLR9 in antibiotic-treated groups and TLR6 was also up-regulated by the immunomodulatory tetracyclines with higher efficacy (doxycycline, minocycline and tigecycline).
CONCLUSION
The anti-inflammatory effect of tetracyclines involves specific modifications in TLR and microRNA expression leading to an improved microbial-derived signalling and mucosal protection. These results support the potential of immunomodulatory tetracyclines to prevent inflammation-associated tissue damage in acute intestinal inflammation.
Topics: Animals; Colitis; Dinitrofluorobenzene; Gastrointestinal Microbiome; Gene Expression; Immunologic Factors; Male; Mice; MicroRNAs; Tetracyclines
PubMed: 30076847
DOI: 10.1016/j.bcp.2018.07.044 -
Cellular Immunology 2014Dendritic cells (DCs) link the sensing of the environment by the innate immune system to the initiation of adaptive immune responses. Accordingly, DCs are considered to...
Dendritic cells (DCs) link the sensing of the environment by the innate immune system to the initiation of adaptive immune responses. Accordingly, DCs are considered to be a major target in the development of immunomodulating compounds. In this study, the effect of niclosamide, a Food and Drug Administration-approved antihelminthic drug, on the activation of lipopolysaccharide (LPS)-stimulated murine bone marrow-derived DCs was examined. Our experimental results show that niclosamide reduced the pro-inflammatory cytokine and chemokine expression of LPS-activated DCs. In addition, niclosamide also affected the expression of MHC and costimulatory molecules and influenced the ability of the cells to take up antigens. Therefore, in mixed cell cultures composed of syngeneic OVA-specific T cells and DCs, niclosamide-treated DCs showed a decreased ability to stimulate T cell proliferation and IFN-γ production. Furthermore, intravenous injection of niclosamide also attenuated contact hypersensitivity (CHS) in mice during sensitization with 2,4-dinitro-1-fluorobenzene. Blocking the LPS-induced activation of MAPK-ERK, JNK and NF-κB may contribute to the inhibitory effect of niclosamide on DC activation. Collectively, our findings suggest that niclosamide can manipulate the function of DCs. These results provide new insight into the immunopharmacological role of niclosamide and suggest that it may be useful for the treatment of chronic inflammatory disorders or DC-mediated autoimmune diseases.
Topics: Animals; Anthelmintics; Bone Marrow Cells; Cell Proliferation; Cells, Cultured; Coculture Techniques; Dendritic Cells; Dinitrofluorobenzene; Female; Gene Expression Regulation; Hypersensitivity; Immunization; Immunomodulation; Injections, Intravenous; Lipopolysaccharides; Lymphocyte Activation; MAP Kinase Kinase 4; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase Kinases; NF-kappa B; Niclosamide; Signal Transduction; T-Lymphocytes
PubMed: 24561310
DOI: 10.1016/j.cellimm.2013.12.006 -
Particle and Fibre Toxicology Jan 2019The effects of carbon nanotubes on skin toxicity have not been extensively studied; however, our lab has previously shown that a carboxylated multi-walled carbon...
BACKGROUND
The effects of carbon nanotubes on skin toxicity have not been extensively studied; however, our lab has previously shown that a carboxylated multi-walled carbon nanotube (MWCNT) exacerbates the 2, 4-dinitrofluorobenzene induced contact hypersensitivity response in mice. Here we examine the role of carboxylation in MWCNT skin toxicity.
RESULTS
MWCNTs were analyzed by transmission electron microscopy, zetasizer, and x-ray photoelectron spectroscopy to fully characterize the physical properties. Two MWCNTs with different levels of surface carboxylation were chosen for further testing. The MWCNTs with a high level of carboxylation displayed increased cytotoxicity in a HaCaT keratinocyte cell line, compared to the MWCNTs with intermediate levels of carboxylation. However, neither functionalized MWCNT increased the level of in vitro reactive oxygen species suggesting an alternative mechanism of cytotoxicity. Each MWCNT was tested in the contact hypersensitivity model, and only the MWCNTs with greater than 20% surface carboxylation exacerbated the ear swelling responses. Analysis of the skin after MWCNT exposure reveals that the same MWCNTs with a high level of carboxylation increase epidermal thickness, mast cell and basophil degranulation, and lead to increases in polymorphonuclear cell recruitment when co-administered with 2, 4-dinitrofluorobenzene.
CONCLUSIONS
The data presented here suggest that acute, topical application of low doses of MWCNTs can induce keratinocyte cytotoxicity and exacerbation of allergic skin conditions in a carboxylation dependent manner.
Topics: Animals; Carboxylic Acids; Cell Degranulation; Cell Line; Cell Survival; Cytokines; Dermatitis, Contact; Dinitrofluorobenzene; Edema; Humans; Keratinocytes; Mice, Hairless; Mice, Inbred C57BL; Nanotubes, Carbon; Neutrophil Infiltration; Oxidation-Reduction; Skin
PubMed: 30621720
DOI: 10.1186/s12989-018-0285-x -
Journal of Controlled Release :... Aug 2012The objective of the present study was to investigate the effect of polyarginine chain length on topical delivery of surface modified NLCs. Design of experiments (DOE)...
The objective of the present study was to investigate the effect of polyarginine chain length on topical delivery of surface modified NLCs. Design of experiments (DOE) was used to optimize number of arginines required to deliver active drug into deeper skin layers. The NLCs were prepared by hot-melt technique and the surface of NLCs was modified with six-histidine tagged cell penetrating peptides (CPPs) or YKA. In vivo confocal microscopy and Raman confocal spectroscopy studies were performed using fluorescent dye encapsulated NLCs and NLC-CPPs. Spantide II (SP) and ketoprofen (KP) were used as model drugs for combined delivery. In vitro skin permeation and drug release studies were performed using Franz diffusion cells. Inflammatory response corresponding to higher skin permeation was investigated in allergic contact dermatitis (ACD) mouse model. NLCs had a particle size of 140±20nm with higher encapsulation efficiencies. The negative charge of NLC was reduced from -17.54 to -8.47 mV after surface modification with CPPs. In vivo confocal microscopy and Raman confocal spectroscopy studies suggested that a peptide containing 11 arginines (R11) had significant permeation enhancing ability than other polyarginines and TAT peptides. The amount of SP and KP retained in dermis after topical application of NLC-R11 was significantly higher than solution and NLC after 24 h of skin permeation. SP was not found in receiver compartment. However, KP was found in receiver compartment and the amount of KP present in receiver compartment was increased approximately 7.9 and 2.6 times compared to the control solution and NLCs, respectively. In an ACD mouse model, SP+KP-NLC-R11 showed significant reduction (p<0.05) in ear thickness compared to SP+KP solution and SP+KP-NLC. Our results strongly suggest that the surface modification of NLC with R11 improved transport of SP and KP across the deeper skin layers and thus results in reduction of inflammation associated with ACD.
Topics: Administration, Topical; Allergens; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell-Penetrating Peptides; Dermatitis, Allergic Contact; Dinitrofluorobenzene; Drug Carriers; Ketoprofen; Lipids; Male; Mice; Mice, Inbred C57BL; Nanoparticles; Oligopeptides; Peptides; Rats; Rats, Hairless; Skin Absorption; Substance P
PubMed: 22617521
DOI: 10.1016/j.jconrel.2012.05.011 -
European Journal of Immunology Jan 2017Accumulating evidence suggests that activated mast cells are involved in contact hypersensitivity, although the precise mechanisms of their activation are still not...
Accumulating evidence suggests that activated mast cells are involved in contact hypersensitivity, although the precise mechanisms of their activation are still not completely understood. We investigated the potential of common experimental allergens to induce mast cell activation using murine bone marrow-derived cultured mast cells and rat peritoneal mast cells. Among these allergens, 1-chloro-2,4-dinitrobenzene and 1-fluoro-2,4-dinirobenzene (DNFB) were found to induce degranulation of rat peritoneal mast cells. DNFB-induced degranulation is accompanied by cytosolic Ca mobilization and is significantly inhibited by pertussis toxin, U73122 (a phospholipase C inhibitor), and BAPTA (a Ca chelator), raising the possibility that DNFB acts on the G protein-coupled receptors and activates G , which induces activation of phospholipase C, as well as known mast cell secretagogues, such as compound 48/80. DNFB could induce mast cell degranulation in the absence of serum proteins and IgE. Structure-activity relationship analyses revealed an inverse correlation between the degree of degranulation and the electron density of the C1 carbon of the DNFB derivatives. These findings raise a possibility that DNFB functions as a potent contact allergen through induction of cutaneous mast cell degranulation.
Topics: Allergens; Animals; Calcium; Cell Degranulation; Cytokines; Dinitrofluorobenzene; GTP-Binding Proteins; Male; Mast Cells; Mice; Molecular Structure; Protein Binding; Protein Multimerization; Rats; Signal Transduction; Type C Phospholipases
PubMed: 27748951
DOI: 10.1002/eji.201646536 -
The Journal of Investigative Dermatology Jul 1980Epidermal Langerhans cells exhibit many features of macrophages/monocytes. Both bear surface receptors for the Fc portion of immunoglobulin molecules and the C3b...
Epidermal Langerhans cells exhibit many features of macrophages/monocytes. Both bear surface receptors for the Fc portion of immunoglobulin molecules and the C3b complement component. Both take up, process, and present antigens to reactive lymphocytes in an effective fashion, and they display on their cell surfaces the alloantigenic determinants encoded by the I region of the major histocompatibility complex. In view of these facts, we explored the extent to which cutaneous sites with unusual immunologic attributes might correspondingly have maldistributions or decreased surface densities of Langerhans cells. Common body sites such as the ear, back, and abdominal wall skin in hamsters, mice, and guinea pigs had regularly distributed ATPase-positive Langerhans cells in surface densities between 500 and 1,500 cells/mm2. In contrast, hamster cheek pouch epithelium had fewer than 200 Langerhans cells/mm2 and murine tail skin exhibited both a decreased density and an unusual gridlike distribution of the cells. Langerhans cells were never demonstrated in corneal epithelium. Perturbation of body wall skin with ultraviolet light and with dinitrofluorobenzene temporarily depleted the skin of ATPase-positive Langerhans cells. Heterotopic grafts of hamster cheek pouch and murine tail skin tended to accumulate Langerhans cells and to become more like body wall skin. The concordance of Langerhans cell aberrations and unusual immunologic features of corneal cheek pouches and tail skins suggests the possibility that intentional perturbations of surface Langerhans cells, as with UVL, might achieve unusual immunologic reactions within normal body wall skin.
Topics: Adenosine Triphosphatases; Animals; Cheek; Cornea; Cricetinae; Dermatitis, Contact; Dinitrofluorobenzene; Guinea Pigs; Immunization; Langerhans Cells; Mesocricetus; Mice; Nitrobenzenes; Skin; Skin Transplantation; Tail; Transplantation, Homologous; Ultraviolet Rays
PubMed: 6446586
DOI: 10.1111/1523-1747.ep12521261 -
Journal of Controlled Release :... Mar 2012The objective of the present study was to evaluate the effect of oleic acid modified polymeric bilayered nanoparticles (NPS) on combined delivery of two...
The objective of the present study was to evaluate the effect of oleic acid modified polymeric bilayered nanoparticles (NPS) on combined delivery of two anti-inflammatory drugs, spantide II (SP) and ketoprofen (KP) on the skin permeation. NPS were prepared using poly(lactic-co-glycolic acid) (PLGA) and chitosan. SP and KP were encapsulated in different layers alone or/and in combination (KP-NPS, SP-NPS and SP+KP-NPS). The surface of NPS was modified with oleic acid (OA) ('Nanoease' technology) using an established procedure in the laboratory (KP-NPS-OA, SP-NPS-OA and SP+KP-NPS-OA). Fluorescent dyes (DiO and DID) containing surface modified (DiO-NPS-OA and DID-NPS-OA) and unmodified NPS (DiO-NPS and DID-NPS) were visualized in lateral rat skin sections using confocal microscopy and Raman confocal spectroscopy after skin permeation. In vitro skin permeation was performed in dermatomed human skin and HPLC was used to analyze the drug levels in different skin layers. Further, allergic contact dermatitis (ACD) model was used to evaluate the response of KP-NPS, SP-NPS, SP+KP-NPS, KP-NPS-OA, SP-NPS-OA and SP+KP-NPS-OA treatment in C57BL/6 mice. The fluorescence from OA modified NPS was observed up to a depth of 240μm and was significantly higher as compared to non-modified NPS. The amount of SP and KP retained in skin layers from OA modified NPS increased by several folds compared to unmodified NPS and control solution. In addition, the combination index value calculated from ACD response for solution suggested an additive effect and moderate synergism for NPS-OA. Our results strongly suggest that surface modification of bilayered nanoparticles with oleic acid improved drug delivery to the deeper skin layers.
Topics: Administration, Cutaneous; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Dermatitis, Allergic Contact; Dinitrofluorobenzene; Humans; Ketoprofen; Lactic Acid; Male; Mice; Mice, Inbred C57BL; Nanoparticles; Oleic Acid; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Rats; Skin; Skin Absorption; Substance P; Succinimides
PubMed: 22134117
DOI: 10.1016/j.jconrel.2011.11.016 -
Mediators of Inflammation 2016The leaves of Artemisia argyi Lev. et Vant. and A. princeps Pamp. are well known medicinal herbs used to treat patients in China, Japan, and Korea with skin problems...
The leaves of Artemisia argyi Lev. et Vant. and A. princeps Pamp. are well known medicinal herbs used to treat patients in China, Japan, and Korea with skin problems such as eczema and itching, as well as abdominal pain and dysmenorrhoea. We investigated the anti-inflammatory effects of Artemisia leaf extract (ALE) using CD mice and Raw 264.7 cells. The effects of ALE on histopathological changes and cytokine production in ear tissues were assessed in mice with CD induced by 1-fluoro-2,4-dinitrobenzene (DNFB). Moreover, the anti-inflammatory effects on production levels of prostaglandin E2 (PGE2) and nitric oxide (NO) and expression levels of cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS) were investigated in Raw 264.7 cells. Topical application of ALE effectively prevented ear swelling induced by repeated DNFB application. ALE prevented epidermal hyperplasia and infiltration of immune cells and lowered the production of interferon- (IFN-) gamma (γ), tumour necrosis factor- (TNF-) alpha (α), and interleukin- (IL-) 6 in inflamed tissues. In addition, ALE inhibited expression of COX-2 and iNOS and production of NO and PGE2 in Raw 264.7 cells. These results indicate that Artemisia leaf can be used as a therapeutic agent for inflammatory skin diseases and that its anti-inflammatory effects are closely related to the inhibition of inflammatory mediator release from macrophages and inflammatory cytokine production in inflamed tissues.
Topics: Animals; Anti-Inflammatory Agents; Artemisia; China; Cyclooxygenase 2; Cytokines; Dermatitis, Contact; Dinitrofluorobenzene; Dinoprostone; Epidermis; Hyperplasia; Inflammation; Interferon-gamma; Interleukin-6; Macrophages; Male; Mice; Mice, Inbred BALB C; Nitric Oxide Synthase Type II; Plant Extracts; Plant Leaves; RAW 264.7 Cells; Tumor Necrosis Factor-alpha
PubMed: 27647952
DOI: 10.1155/2016/8027537