The closure of skin wounds is essential for resistance against microbial pathogens, and keratinocyte migration is an important step in skin wound healing. Cathelicidin hCAP18/LL-37 is an innate antimicrobial peptide that is expressed in the skin and acts to eliminate microbial pathogens. Because hCAP18/LL-37 is up-regulated at skin wound sites, we hypothesized that LL-37 induces keratinocyte migration. In this study, we found that 1 μg/ml LL-37 induced the maximum level of keratinocyte migration in the Boyden chamber assay. In addition, LL-37 phosphorylated the epidermal growth factor receptor (EGFR) after 10 min, which suggests that LL-37-induced keratinocyte migration occurs via EGFR transactivation. To test this assumption, we used inhibitors that block the sequential steps of EGFR transactivation, such as OSU8-1, CRM197, anti-EGFR no. 225 Ab, and AG1478. All of these inhibitors completely blocked LL-37-induced keratinocyte migration, which indicates that migration occurs via HB-EGF-mediated EGFR transactivation. Furthermore, CRM197, anti-EGFR no. 225, and AG1478 blocked the LL-37-induced phosphorylation of STAT3, and transfection with a dominant-negative mutant of STAT3 abolished LL-37-induced keratinocyte migration, indicating the involvement of the STAT3 pathway downstream of EGFR transactivation. Finally, we tested whether the suppressor of cytokine signaling (SOCS)/cytokine-inducible Src homology 2-containing protein (CIS) family of negative regulators of STAT3 regulates LL-37-induced keratinocyte migration. Transfection with SOCS1/Jak2 binding protein or SOCS3/CIS3 almost completely abolished LL-37-induced keratinocyte migration. In conclusion, LL-37 induces keratinocyte migration via heparin-binding-EGF-mediated transactivation of EGFR, and SOCS1/Jak 2 binding and SOCS3/CIS3 negatively regulate this migration. The results of this study suggest that LL-37 closes skin wounds by the induction of keratinocyte migration.

Geographic atrophy is a blinding form of age-related macular degeneration characterized by death of the retinal pigmented epithelium (RPE). In this disease, the RPE displays evidence of DICER1 deficiency, resultant accumulation of endogenous Alu retroelement RNA, and NLRP3 inflammasome activation. How the inflammasome is activated in this untreatable disease is largely unknown. Here we demonstrate that RPE degeneration in human cell culture and in mouse models is driven by a non-canonical inflammasome pathway that results in activation of caspase-4 (caspase-11 in mice) and caspase-1, and requires cyclic GMP-AMP synthase (cGAS)-dependent interferon-β (IFN-β) production and gasdermin D-dependent interleukin-18 (IL-18) secretion. Reduction of DICER1 levelsor accumulation of Alu RNA triggers cytosolic escape of mitochondrial DNA, which engages cGAS. Moreover, caspase-4, gasdermin D, IFN-β, and cGAS levels are elevated in the RPE of human eyes with geographic atrophy. Collectively, these data highlight an unexpected role for cGAS in responding to mobile element transcripts, reveal cGAS-driven interferon signaling as a conduit for mitochondrial damage-induced inflammasome activation, expand the immune sensing repertoire of cGAS and caspase-4 to non-infectious human disease, and identify new potential targets for treatment of a major cause of blindness.

Recent studies revealed that two novel interleukin (IL)-12-related cytokines, IL-23 and IL-27, have potent antitumor activities. However, the antitumor effects were mainly evaluated in relatively highly immunogenic tumors and have not been fully evaluated against nonimmunogenic or poorly immunogenic tumors. In this study, we investigated the antitumor efficacies of IL-23 and IL-27 on poorly immunogenic B16F10 melanoma and found that the antitumor responses mediated by IL-23 and IL-27 were clearly different. In syngeneic mice, mouse single-chain (sc) IL-23-transfected B16F10 (B16/IL-23) tumors exhibited almost the same growth curve as B16F10 parental tumor about until day 20 after tumor injection and then showed growth inhibition or even regression. In contrast, scIL-27-transfected B16F10 (B16/ IL-27) tumors exhibited significant retardation of tumor growth from the early stage. In vivo depletion assay revealed that the antitumor effect of B16/IL-23 was mainly mediated by CD8 + T cells and IFN-; whereas that of B16/IL-27 mainly involved natural killer cells and was independent of IFN-;. We also found that antitumor effects of B16/IL-23 and B16/IL-27 were synergistically enhanced by treatment with IL-18 and IL-12, respectively. Furthermore, B16/IL-23-vaccinated mice developed protective immunity against parental B16F10 tumors but B16/IL-27-vaccinated mice did not. When combined with prior in vivo depletion of CD25 + T cells, 80% of B16/ IL-23-vaccinated mice completely rejected subsequent tumor challenge. Finally, we showed that the systemic administration of neither IL-23 nor IL-27 induced such intense toxicity as IL-12. Our data support that IL-23 and IL-27 might play a role in future cytokine-based immunotherapy against poorly immunogenic tumors. (Cancer Res 2006; 66(12): 6395-404)

( ) Trabalho apresentado no 14° Congresso Brasileiro de Entomologia, Piracicaba (SP), 1993. Recebido para publicação em 14 de setembro de 1993 e aceito em 9 de fevereiro de 1994.( RESUMOA partir de 1991, tem sido observada a presença da mosca-branca Bemisia tabaci (Genn.) (Homoptera: Aleyrodidae) em altas populações em hortaliças e ornamentais nos municípios paulistas de Paulínia, Holambra, Jaguariúna e Artur Nogueira. Foram constatadas infestações severas em tomateiro, brócolos, berinjela e aboboreira; nesta última, o sintoma observado em plantas infestadas pela mosca-branca é o prateamento da face superior das folhas, em conjunto com queda drástica da produção. Uma lavoura de tomate severamente infestada por B. tabaci apresentava o sintoma referido como amadurecimento irregular dos frutos do tomateiro; plantas invasoras presentes nessa área também foram intensamente colonizadas, principalmente Sida rhombifolia L., Sonchus oleraceus L., Solarium viarum Dun. e Ipomoea acuminata Roem. & Schult. Em Holambra, verificaram-se ataques intensos em plantas ornamentais, principalmente crisântemo (Chrysantemum morifolium Ramat.) e bico-de-papagaio {Euphorbia pulcherrima Willd.); roseiras foram pouco colonizadas. Nessas hortaliças e nas ornamentais, a aplicãçfo' quase diária de inseticidas não reduziu a infestação do inseto. Além dessas plantas, campos de algodão, em Holambra, e de feijão, em Paulínia, também foram infestados por B. tabaci. Nos E.U.A., a capacidade de certas populações de B. tabaci de induzir o prateamento da folha em aboboreira e de colonizar intensamente E. pulcherrima, entre outros fatores, têm levado à distinção do biótipo "B" ou "poinsétia", nome vulgar dessa euforbiácea; todavia, estudos recentes na Califórnia (E.U.A.) mostram a possibilidade de se tratar de duas espécies distintas. Dada a silimaridade entre as infestações associadas a B. tabaci que vêm ocorrendo naquele país e, mais recentemente, no Brasil, é provável que o biótipo B ou essa nova espécie tenha sido aqui introduzido. Termos de indexação:Insecta, mosca-branca, Aleyrodidae, folha-prateada-da-aboboreira, amadurecimento irregular dos frutos do tomateiro, anomalias, poinsétia, Euphorbia pulcherrima. ABSTRACT OUTBREAKS OF BEMISIA TABACI IN THE SÃO PAULO STATE, BRAZILSince 1991, an increase in the populations of the whitefly Bemisia tabaci (Genn.) (Homoptera: Aleyrodidae) infesting vegetables and ornamental plants in some localities of São Paulo State, Brazil, has been observed. High densities of this insect were verified on tomato, broccoli, egg-plant and squash; in some cases, tomato and squash presented the whitefly-related disorders named tomato irregular repening and squash silverleaf. Weeds, mainly Sida rhombifolia L., Sonchus oleraceus L., Solanum viarum Dun. and Ipomoea acuminata Roem. & Schult., showed high whitefly colonization. At the Holambra county intensive colonizations were recorded on ornamental plants, mainly Chrysanthemum morifolium Ramat. and Euphorbia pulcherrima Willd. (poinsettia). Daily insecticide applications did ...

IL-27 is a member of the IL-6/IL-12 family and activates both STAT1 and STAT3 through its receptor, which consists of WSX-1 and gp130. We previously demonstrated that IL-27 has potent antitumor activities, which are mediated through CD8+ T cells, NK cells, or its own antiangiogenic activity. In this study, we demonstrate that IL-27 also possesses a direct antiproliferative activity on melanoma. Although WSX-1 expression was hardly detected in parental mouse melanoma B16F10 cells, IL-27 activated STAT1 and STAT3 and up-regulated MHC class I in B16F10 transfectants expressing wild-type WSX-1. In contrast, IL-27 failed to activate STAT1 and up-regulate MHC class I in those expressing mutant WSX-1, in which the putative STAT1-binding Tyr-609 of the cytoplasmic region was replaced by Phe. IL-27 inhibited the tumor growth of transfectants expressing wild-type WSX-1 in a dose-dependent manner. IL-27 augmented the expression of IFN regulatory factor (IRF)-1 and IRF-8, which possess tumor suppressor activities, in B16F10 transfectants expressing wild-type WSX-1. Down-regulation of IRF-1 but not IRF-8 with small interfering RNA partially blocked the IL-27-induced growth inhibition. A small, but significant, direct antiproliferative effect of IL-27 was also observed in vivo. Moreover, several human melanoma cells were revealed to express both IL-27 receptor subunits, and activation of STAT1 and STAT3 and growth inhibition by IL-27 were detected. These results suggest that IL-27 has an antiproliferative activity on melanomas through WSX-1/STAT1 signaling. Thus, IL-27 may be an attractive candidate as an antitumor agent applicable to cancer immunotherapy.