Kana Masuda

Cefcapene Pivoxil Hydrochloride Is a Potentially New Treatment for Palmoplantar Pustulosis with Pustulotic Arthro-Osteitis.

Pustulosis palmaris et plantaris or palmoplantar pustulosis (PPP) is a refractory pustular eruption of the palms and soles with unknown etiology. In addition to skin lesions, PPP patients may present with severe joint pain and pustulotic arthro-osteitis (PAO), especially of the sternoclavicular joint. PAO is sometimes regarded as a variant of synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome. Hence, macrolide and tetracycline antibiotics are used for the treatment of PPP with PAO. We report 3 cases of PPP with PAO that did not improve upon administration of macrolide antibiotics with NSAIDs. After administration of cefcapene pivoxil hydrochloride (CFPN-PI), a third-generation cephalosporin, the swelling and sternoclavicular joint pain were promptly reduced and dramatically improved in all 3 cases. We review the conventional antibiotic treatments used currently and propose CFPN-PI as a potentially new therapy for PPP or PPP + PAO.

Reduced-HMGB1 suppresses poly(I:C)-induced inflammation in keratinocytes

BACKGROUND High mobility group box 1 (HMGB1) is a nuclear protein that stabilizes DNA and facilitates gene transcription. Additionally, cell stress or death induces the release of HMGB1 outside the cell membrane, where HMGB1 functions as an alarmin, causing an inflammatory response in combination with other cytokines, damage-associated molecular patterns (DAMPs), and pathogen-associated molecular patterns (PAMPs). OBJECTIVE To evaluate the effect of reduced-HMGB1 (previously termed chemoattractive-HMGB1) on polyinosine-polycytidylic acid [poly(I:C)]-induced inflammation in normal human keratinocytes (NHKs). METHODS We focused on downstream components of the poly(I:C)-Toll-like receptor 3 (TLR3), retinoic acid-inducible gene-I (RIG-I), and melanoma differentiation-associated protein 5 (MDA5) pathways, including IκBα, nuclear factor (NF)-κB p65, mitogen-activated protein kinase (MAPK), and interferon regulatory factor 3 (IRF3), and assessed whether these pathways are involved in the suppression of poly(I:C)-induced inflammation in NHKs by HMGB1. An immunoprecipitation was performed to know whether HMGB1 could bind to poly(I:C), and immunofluorescence staining and flow cytometric analysis were performed to check whether reduced-HMGB interferes with cellular uptake of poly(I:C) translocation (possibly by endocytosis). RESULTS Application of exogenous HMGB1 before, but not after, exerted a suppressive effect on poly(I:C)-induced inflammation in NHKs. In addition, reduced-HMGB1, but not disulfide-HMGB1, exerted a suppressive effect on poly(I:C)-induced inflammation in NHKs, suggesting the importance of the redox status of exogenous HMGB1. Pre-treatment with reduced-HMGB1 inhibited the phosphorylation of IκBα, NF-κB p65, and IRF3 induced by poly(I:C) stimulation in NHKs; however, phosphorylation of p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) was unaffected. Disulfide-HMGB1 formed a complex with poly(I:C), as did reduced- and oxidized-HMGB1, albeit to a lesser extent. Immunofluorescence staining and flow cytometric analysis indicated that reduced-HMGB interferes with cellular uptake of poly(I:C) translocation (possibly by endocytosis). CONCLUSION These findings suggest that pre-treatment with reduced-HMGB1 ameliorates poly(I:C)-mediated inflammation in NHKs.

Heparinoid suppresses Der p-induced IL-1β production by inhibiting ERK and p38 MAPK pathways in keratinocytes

Epidermal keratinocytes initiate skin inflammation by activating immune cells. The skin barrier is disrupted in atopic dermatitis (AD) and epidermal keratinocytes can be exposed to environmental stimuli, such as house dust mite (HDM) allergens. We showed previously that HDM allergens activate the NLRP3 inflammasome of keratinocytes, thereby releasing pro‐inflammatory cytokines. Heparinoid is an effective moisturizer for atopic dry skin. However, a recent report showed that heparinoid treatment can improve inflammation of lichen planus. Therefore, we hypothesized that it acts on epidermal keratinocytes not only as a moisturizer, but also as a suppressant of the triggers of skin inflammation. We found that HDM allergen‐induced interleukin (IL)‐1β release from keratinocytes was inhibited significantly by heparinoid pretreatment without affecting cell viability. However, heparinoid did not affect caspase‐1 release, suggesting that heparinoid did not affect HDM allergen‐induced inflammasome activation. Heparinoid treatment not only decreased intracellular levels of pro‐IL‐1β, but also suppressed IL‐1β messenger RNA (mRNA) expression in keratinocytes. Among the intracellular signalling pathways, the activation of extracellular signal‐regulated kinase and p38 pathways, which are required for IL‐1β expression in keratinocytes, was inhibited by heparinoid treatment. The inhibitory effect of heparinoid on IL‐1β mRNA expression was also confirmed with living skin equivalents. Our results demonstrated that heparinoid suppresses the initiation of keratinocyte‐mediated skin inflammation.

Bcl-3 induced by IL-22 via STAT3 activation acts as a potentiator of psoriasis-related gene expression in epidermal keratinocytes

IL‐22 induces STAT3 phosphorylation and mediates psoriasis‐related gene expression. However, the signaling mechanism leading from pSTAT3 to the expression of these genes remains unclear. We focused on Bcl‐3, which is induced by STAT3 activation and mediates gene expression. In cultured human epidermal keratinocytes, IL‐22 increased Bcl‐3, which was translocated to the nucleus with p50 via STAT3 activation. The increases in CXCL8, S100As and human β‐defensin 2 mRNA expression caused by IL‐22 were abolished by siRNA against Bcl‐3. Although CCL20 expression was also augmented by IL‐22, the knockdown of Bcl‐3 increased its level. Moreover, the combination of IL‐22 and IL‐17A enhanced Bcl‐3 production, IL‐22‐induced gene expression, and the expression of other psoriasis‐related genes, including those encoding IL‐17C, IL‐19, and IL‐36γ. The expression of these genes (except for CCL20) was also suppressed by the knockdown of Bcl‐3. Bcl‐3 overexpression induced CXCL8 and HBD2 expression but not S100As expression. We also compared Bcl‐3 expression between psoriatic skin lesions and normal skin. Immunostaining revealed strong signals for Bcl‐3 and p50 in the nucleus of epidermal keratinocytes from psoriatic skin. The IL‐22‐STAT3‐Bcl‐3 pathway may be important in the pathogenesis of psoriasis.

TLN-58, an Additional hCAP18 Processing Form, Found in the Lesion Vesicle of Palmoplantar Pustulosis in the Skin

We previously reported that the early vesicle of the palmoplantar pustulosis (PPP) vesicle originated from eccrine sweat in the acrosyringium and that the PPP vesicle contains the antimicrobial peptide human cathelicidin-18/LL-37. The concentration of LL-37 was sufficient to induce the subsequent inflammation in lesions and human keratinocytes, and the PPP vesicles contained additional small fragments of human cathelicidin-18, of approximately 7 kDa, which have not been identified. The aim of the present study was to clarify the additional processed forms found in PPP vesicles and their physiological effects on normal keratinocytes and sweat gland cells. Lesional PPP vesicles were collected from PPP patients, and endogenous human cathelicidin-18/LL-37 was depleted using a LL-37 antibody affinity column. A designed recombinant human cathelicidin-18 peptide was prepared and incubated with the depleted PPP vesicle fluid to confirm the additional processed form. In-gel digestion analysis and protein sequencing confirmed the additional form as TLN-58. TLN-58 up-regulated IL-17C, IL-8, IL-23, IL-1α, and IL-1β mRNA and protein expression in normal human keratinocytes and also showed antibacterial activity against Staphylococcus aureus, Staphylococcus epidermidis, and group A Streptococcus species, similar to LL-37. This additional form could be involved in the continued inflammation in PPP lesions.

Case of palmoplantar pustulosis that developed with acute glomerulonephritis.

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