Detrimental Role of CXCR3 in α-Naphthylisothiocyanate- and Triptolide-Induced Cholestatic Liver Injury.

The chemokine receptor CXCR3 is functionally pleiotropic, not only recruiting immune cells to the inflamed liver but also mediating the pathological process of cholestatic liver injury (CLI). However, the mechanism of its involvement in the CLI remains unclear. Both alpha-naphthylisothiocyanate (ANIT) and triptolide are hepatotoxicants that induce CLI by bile acid (BA) dysregulation, inflammation, and endoplasmic reticulum (ER)/oxidative stress. Through molecular docking, CXCR3 is a potential target of ANIT and triptolide. Therefore, this study aimed to investigate the role of CXCR3 in ANIT- and triptolide-induced CLI and to explore the underlying mechanisms. Wild-type mice and CXCR3-deficient mice were administered with ANIT or triptolide to compare CLI, BA profile, hepatic recruitment of IFN-γ/IL-4/IL-17+CD4+T cells, IFN-γ/IL-4/IL-17+iNKT cells and IFN-γ/IL-4+NK cells, and the expression of ER/oxidative stress pathway. The results showed that CXCR3 deficiency ameliorated ANIT- and triptolide-induced CLI. CXCR3 deficiency alleviated ANIT-induced dysregulated BA metabolism, which decreased the recruitment of IFN-γ+NK cells and IL-4+NK cells to the liver and inhibited ER stress. After triptolide administration, CXCR3 deficiency ameliorated dysregulation of BA metabolism, which reduced the migration of IL-4+iNKT cells and IL-17+iNKT cells and reduced oxidative stress through inhibition of Egr1 expression and AKT phosphorylation. Our findings suggest a detrimental role of CXCR3 in ANIT- and triptolide-induced CLI, providing a promising therapeutic target and introducing novel mechanisms for understanding cholestatic liver diseases.

Adjuvant effect of inhaled particulate matter containing free radicals following house-dust mite induction of asthma in mice.

INTRODUCTION: Exposures to particulate matter (PM) from combustion sources can exacerbate preexisting asthma. However, the cellular and molecular mechanisms by which PM promotes the exacerbation of asthma remain elusive. We used a house dust mite (HDM)-induced mouse model of asthma to test the hypothesis that inhaled DCB230, which are PM containing environmentally persistent free radicals (EPFRs), will aggravate asthmatic responses. METHODS: Groups of 8-10-week-old C57BL/6 male mice were exposed to either air or DCB230 aerosols at a concentration of 1.5 mg/m3 4 h/day for 10 days with or without prior HDM-induction of asthma. RESULTS: Aerosolized DCB230 particles formed small aggregates (30-150 nm). Mice exposed to DCB230 alone showed significantly reduced lung tidal volume, overexpression of the Muc5ac gene, and dysregulation of 4 inflammation related genes, Ccl11, Ccl24, Il-10, and Tpsb2. This suggests DCB230 particles interacted with the lung epithelium inducing mucous hypersecretion and restricting lung volume. In addition to reduced lung tidal volume, compared to respective controls, the HDM + DCB230-exposed group exhibited significantly increased lung tissue damping and up-regulated expression of Muc5ac, indicating that in this model, mucous hypersecretion may be central to pulmonary dysfunction. This group also showed augmented lung eosinophilic inflammation accompanied by an up-regulation of 36 asthma related genes. Twelve of these genes are part of IL-17 signaling, suggesting that this pathway is critical for DCB230 induced toxicity and adjuvant effects in lungs previously exposed to HDM. CONCLUSION: Our data indicate that inhaled DCB230 can act as an adjuvant, exacerbating asthma through IL-17-mediated responses in a HDM mouse model.

Comparative protein profiling reveals the inhibitory role of curcumin on IL-17A mediated minichromosome maintenance (MCM) proteins as novel putative markers for acute lung injury in vivo.

The Pro-inflammatory cytokine, Interleukin 17A (IL-17A) plays a vital role in the pathogenesis of inflammatory-induced acute lung injury (ALI). But, the mechanisms of this pro-inflammatory cytokine in response to activation after replication stress are not yet known. Control on DNA replication (DR) is vital for maintaining genome stability. Minichromosome maintenance (MCM) proteins play essential roles in various cancers, but their involvement during ALI is not yet been discussed. The present study was carried out to assess the participation of IL-17A during replication stress and to evaluate the contribution of curcumin on this. Mass spectrometry-based proteomic approach has been used on mice lung tissues treated with IL-17A, as a prime mediator to cause injury and curcumin a natural polyphenol as an intervention. Several trends were identified from the proteomic subset which revealed that IL-17A induces expressions of proteins like MCM2, MCM3, and MCM6 along with other proteins involved in DR. Interestingly, curcumin was found in suppressing the expression levels of these proteins. This was also confirmed via validating LC-MS/MS data using appropriate molecular techniques. Pathway and gene ontology analysis were performed with DAVID GO databases. Apart from this, the present study also reports the unique contribution of curcumin in suppressing the mRNA levels of other MCMs like MCM4, MCM5, and MCM7 as well as of ORC1 and ORC2. Hence, the present study revolves around linking the replication stress by pro-inflammatory effects, highlighting the implications for ALI and therapies. This study, therefore, enhances our capacity to therapeutically target DR-specific proteins.

Downregulation of Cathepsin B Reduces Proliferation and Inflammatory Response and Facilitates Differentiation in Human HaCaT Keratinocytes, Ameliorating IL-17A and SAA-Induced Psoriasis-Like Lesion.

Psoriasis is a common inflammatory dermatology disease. Strongly expressed serum amyloid A (SAA) promotes psoriasis exacerbation through inducing IL-17 secretion. What's more, SAA can stimulate the release of cathepsin B. The current work was performed to demonstrate the specific effects of cathepsin B silencing on inflammatory response, proliferation, and differentiation of IL-17A and SAA-induced keratinocytes and to report the precise role of cathepsin B in psoriasis-like lesion. HaCaT keratinocytes received treatment with IL-17A (0, 10, 50, 100 ng/ml) or SAA (0, 1, 5, 10, 20 µg/ml) for 24 h to establish psoriasis-like keratinocytes model. HaCaT keratinocytes were transfected with small interfering RNA (siRNA)-cathepsin B for the functional experiments. Cathepsin B mRNA and protein levels were separately assessed by performing RT-qPCR and Western blot analysis. Then, CCK-8 for detection of cell proliferative capacity and Western blot assay for detection of Ki67 and PCNA expression were adopted to evaluate the influence of silenced cathepsin B on proliferation of IL-17A/SAA-induced HaCaT keratinocytes. Furthermore, IL-6, IL-1ß, TNF-α, and p-NF-κB p65 were detected to assess the effects of cathepsin B knockdown on inflammatory response in IL-17A/SAA-induced HaCaT keratinocytes. In addition, assessment of KRT10, FLG, and LOR levels were applied to analyze the function of cathepsin B silencing on differentiation of IL-17A/SAA-induced HaCaT keratinocytes. Cathepsin B expression is distinctly elevated in IL-17A/SAA-induced HaCaT keratinocytes. IL-17A or SAA treatment enhanced proliferation, promoted the release of inflammatory factors, and arrested differentiation in HaCaT keratinocytes. Furthermore, downregulation of cathepsin B reduced proliferation, suppressed inflammatory response, and boosted differentiation in IL-17A/SAA-induced HaCaT keratinocytes. To sum up, cathepsin B silencing rescued excessive proliferation and inflammatory response and scarce differentiation in HaCaT keratinocytes induced by IL-17A and SAA. These findings prompted that cathepsin B might be a promising therapeutic target for psoriasis-like lesion, which helps to develop an anti-psoriatic agent.

Interleukin-17 aggravates right ventricular remodeling via activating STAT3 under both normoxia and hypoxia.

OBJECTIVE: Proinflammatory cytokine interleukin 17 (IL-17) is involved in ventricular remodeling, mainly of the left ventricle. This study was designed to explore the role of IL-17 played in the pathogenesis of right ventricular hypertrophy (RVH), aiming to provide a novel treatment target or diagnostic biomarker options for improving the care of RVH patients. METHODS: C57BL/6 mice were maintained in 10% O2 chamber or room air for four weeks. Right ventricular hypertrophy index (RVHI), RV/body weight ratio, pulmonary arteriolar remodeling determined by percent media thickness (%MT), and the cardiomyocyte diameter of RV were evaluated. Mice were treated with exogenous recombinant mouse IL-17 (rmIL-17, 1 µg per dose twice a week) for four weeks. H9c2 cardiomyocytes were cultured and treated with IL-17 (10 ng/mL) and STAT3 inhibitor (10 ng/mL) either under normoxia (21% O2, 5% CO2, 74% N2) or under hypoxia (3% O2, 5% CO2, 92% N2). Cardiomyocyte viability was assessed by Cell counting kit 8 (CCK-8) assay. The mRNA level was detected by RT-PCR, where as the protein expression was measured by Western blot, immunohistochemistry, and immunofluorescent analyses. RESULTS: In vivo experiments showed that IL-17 did not affect the pulmonary artery under normoxia, after treatment with rmIL-17, %MT was not changed, while RVHI and the RV/body weight ratio were increased, indicating that IL-17 directly induced right ventricular hypertrophy. In a time-course study, the mice were exposed to hypoxia for 0, 1, 2, 3, 4 weeks, respectively. We found that the expression of IL-17 was gradually upregulated in RV tissue in a time-dependent manner after one week of hypoxia exposure, especially at the third and fourth week. Cardiomyocyte hypertrophy and apoptosis were observed after the exposure of the mice to hypoxia for four weeks, rmIL-17 further aggravated the hypoxia-induced cardiomyocyte hypertrophy and apoptosis. The expression of p-STAT3 in the IL-17-deficient mice was lower than in the wild-type mice. In vitro, IL-17 inhibited cardiomyocyte viability and induced cardiomyocyte apoptosis via STAT3 under both normoxic and hypoxic conditions. CONCLUSIONS: These findings support a role for IL-17 as a mediator in the pathogenesis RVH, which might be considered as a potential novel anti-inflammation therapeutic strategy or diagnostic biomarker for RVH.

MiR-409-3p and MiR-1896 co-operatively participate in IL-17-induced inflammatory cytokine production in astrocytes and pathogenesis of EAE mice via targeting SOCS3/STAT3 signaling.

Th17 cells and interleukin-17 (IL-17) have been found to play an important role in the pathology of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Response to IL-17, reactive astrocytes accompany with immune cells infiltration and axonal damage in MS/EAE. However, the role and the regulatory mechanism of IL-17-activated astrocytes in inflammation and in the EAE process still remain largely unknown. Here, we elucidated that miR-409-3p and miR-1896, as co-upregulated microRNAs in activated astrocytes and in EAE mice, targeted suppressor of cytokine signaling proteins 3 (SOCS3). Overexpression of miR-409-3p or miR-1896 significantly reduced SOCS3 expression and increased phosphorylation of STAT3 as well as induced the inflammatory cytokines production (IL-1ß, IL-6, IP-10, MCP-1, and KC), CD4+ T cells migration and demyelination, in turn aggravating EAE development. Importantly, the effects of co-overexpression of miR-409-3p and miR-1896 in vitro or in vivo are strongly co-operative. In contrast, simultaneously silenced miR-409-3p and miR-1896 co-operatively ameliorates inflammation and demyelination in the central nervous system of EAE mice. Collectively, our findings highlight that miR-409-3p and miR-1896 co-ordinately promote the production of inflammatory cytokines in reactive astrocytes through the SOCS3/STAT3 pathway and enhance reactive astrocyte-directed chemotaxis of CD4+ T cells, leading to aggravate pathogenesis in EAE mice. Co-inhibition of miR-409-3p and miR-1896 may be a therapeutic target for treating MS and neuroinflammation.

Gallic acid inhibits the expression of keratin 16 and keratin 17 through Nrf2 in psoriasis-like skin disease.

Gallic acid (GA), a natural small molecule found in Radix Paeoniae Rubra, has a variety of favorable biological activities. However, the anti-psoriasis effect of GA has never been explored up to now. This study evaluates the protective effect of GA on psoriasis-like skin disease both in vitro and in vivo and explores the underlying mechanism. The results show that GA significantly decreases the mRNA and protein expression of keratin 16 and keratin 17 which are the markers of psoriasis. Additionally, GA obviously ameliorates psoriasis area and severity index scores and decreases the epidermal hyperplasia of psoriasis-like disease mice. The activity of Nrf2 which targets keratin 16 and keratin 17 is significantly downregulated by GA. Furthermore, the downregulation of keratin 16 and keratin 17 induced by GA was abolished by the Nrf2-overexpression in vitro. This study initially elucidates the anti-psoriasis effect and mechanism of GA which hints that GA would be a potential candidate for the treatment of psoriasis.

Redundant modulatory effects of proinflammatory cytokines in human osteoblastic cells in vitro.

OBJECTIVES: The aim of our study was to investigate possible interaction of IL-17, TRAIL, and TNF-α in the modulation of osteoblast homeostasis in vitro, using human differentiated osteoblastic Saos-2 cells as in vitro model. METHODS: The effects of these cytokines on osteoblastic cell viability were assessed, by MTT assay, alone or in combination, at different times and concentrations. The effects of IL-17 and TNF-α on the regulatory system of osteoclast activity RANK/RANKL/ OPG were evaluated by Western blot and ELISA techniques in cell culture media. Quantitative expression of RANKL, OPG and pro-inflammatory factors were analysed at the mRNA level by quantitative real time RT-PCR. RESULTS: Effects of IL-17, TNF-α and TRAIL on osteoblastic cell viability indicated that IL-17 alone, or in combination with TNF-α did not alter Saos-2 cell viability. On the other hand, TRAIL, as expected, exhibited time- and concentration-dependent cytotoxicity. The expression both RANKL and OPG were increased at the mRNA level and protein release by IL-17 and TNF-α, either alone or in combination. The analysis of IL-17 and TNF-α on pro-inflammatory molecules mRNA expression, such as CXC family chemokines CXCL-1 and CXCL-5, COX-2 and IL-6 demonstrated an increase in these pro-inflammatory cytokines with cooperative effects of the combination. CONCLUSIONS: Overall, these results suggest that IL-17, TRAIL and TNF-α sustain bone tissue inflammation associated with decrease of calcified component. To do so, they act redundantly each other, to amplify the inflammatory response in the bone. In conclusion, unravelling novel molecular targets within the bone-cytokine network represents a platform for innovative treatment of bone diseases due to immunological diseases such as psoriatic arthritis.

IL-17A induces autophagy and promotes microglial neuroinflammation through ATG5 and ATG7 in intracerebral hemorrhage.

Microglial inflammation plays a vital role in intracerebral hemorrhage (ICH)-induced secondary brain injury. IL-17A has been identified to promote microglia activation, but the role in the pathology following ICH remains unclear. Autophagy is involved in modulation of cell metabolism, cell survival, and immune response. However, the role of IL-17A in autophagy following ICH has not been well defined. In this study, we assessed the role of IL-17A in microglial autophagic activity following ICH. The microglia were treated with IL-17A, and then autophagy and inflammation were detected. In addition, RNA interference in essential autophagy genes (ATG5 and ATG7) was also utilized to analyze microglial autophagy in vitro. Furthermore, ICH mice were made by injection of autologous blood model in vivo. And the IL-17A-neutralizing antibody was utilized to assess the neurological scores and brain edema. These data demonstrated that IL-17A promoted microglial autophagy and microglial inflammation. The suppression of autophagy using RNA interference in essential autophagy genes (ATG5 and ATG7) decreased microglial autophagy and inflammation. Moreover, IL-17A Ab significantly reduced brain water content and improved neurological function of ICH mice. Taken together, these data demonstrated that IL-17A promoted microglial autophagy and microglial inflammation, and IL-17A-mediated activation of autophagy might represent novel clues in ICH therapy.

IL-17A induces MIP-1α expression in primary astrocytes via Src/MAPK/PI3K/NF-kB pathways: implications for multiple sclerosis.

Neuroinflammation plays critical roles in multiple sclerosis (MS). In addition to the part played by the lymphocytes, the underlying mechanisms could, in part, be also attributed to activation mediated by astrocytes. Macrophage inflammatory protein-1α (MIP-1α) has been implicated in a number of pathological conditions, specifically attributable to its potent chemottractant effects. Its modulation by IL-17, however, has received very little attention. In the present study, we demonstrated IL-17-mediated induction of MIP-1α in rat primary astroctyes through its binding to the cognate IL-17RA. Furthermore, this effect was mediated via the activation of Src, mitogen-activated protein kinases (MAPKs), PI3K/Akt and NF-kB pathways, culminating ultimately into increased expression of MIP-1α. Exposure of primary mouse astrocytes to IL-17 resulted in increased expression of glial fibrillary acidic protein and, this effect was abrogated in cells cultured in presence of the MIP-1α neutralizing antibody, thus underscoring its role in the activation of astrocytes. In vivo relevance of these findings was further corroborated in experimental autoimmune encephalomyelitis mice that demonstrated significantly increased activation of astrocytes with concomitant increased expression of MIP-1α in the corpus callosum compared with control group. Understanding the regulation of MIP-1α expression may provide insights into the development of potential therapeutic targets for neuroinflammation associated with multiple sclerosis.

Interleukin-17 retinotoxicity is prevented by gene transfer of a soluble interleukin-17 receptor acting as a cytokine blocker: implications for age-related macular degeneration.

Age-related macular degeneration (AMD) is a common yet complex retinal degeneration that causes irreversible central blindness in the elderly. Pathology is widely believed to follow loss of retinal pigment epithelium (RPE) and photoreceptor degeneration. Here we report aberrant expression of interleukin-17A (IL17A) and the receptor IL17RC in the macula of AMD patients. In vitro, IL17A induces RPE cell death characterized by the accumulation of cytoplasmic lipids and autophagosomes with subsequent activation of pro-apoptotic Caspase-3 and Caspase-9. This pathology is reduced by siRNA knockdown of IL17RC. IL17-dependent retinal degeneration in a mouse model of focal retinal degeneration can be prevented by gene therapy with adeno-associated virus vector encoding soluble IL17 receptor. This intervention rescues RPE and photoreceptors in a MAPK-dependent process. The IL17 pathway plays a key role in RPE and photoreceptor degeneration and could hold therapeutic potential in AMD.

Act1 mediates IL-17-induced EAE pathogenesis selectively in NG2+ glial cells.

Interleukin 17 (IL-17) is a signature cytokine of Th17 cells. We previously reported that deletion of NF-κB activator 1 (Act1), the key transducer of IL-17 receptor signaling, from the neuroectodermal lineage in mice (neurons, oligodendrocytes and astrocytes) results in attenuated severity of experimental autoimmune encephalomyelitis (EAE). Here we examined the cellular basis of this observation. EAE disease course was unaffected by deletion of Act1 in neurons or mature oligodendrocytes, and Act1 deletion in astrocytes only modestly affected disease course. Deletion of Act1 in NG2(+) glia resulted in markedly reduced EAE severity. Furthermore, IL-17 induced characteristic inflammatory mediator expression in NG2(+) glial cells. IL-17 also exhibited strong inhibitory effects on the maturation of oligodendrocyte lineage cells in vitro and reduced their survival. These data identify NG2(+) glia as the major CNS cellular target of IL-17 in EAE. The sensitivity of oligodendrocyte lineage cells to IL-17-mediated toxicity further suggests a direct link between inflammation and neurodegeneration in multiple sclerosis.

A CC' loop decoy peptide blocks the interaction between Act1 and IL-17RA to attenuate IL-17- and IL-25-induced inflammation.

Interleukin-17 (IL-17) and IL-25 signaling induce the expression of genes encoding inflammatory factors and are implicated in the pathology of various inflammatory diseases. Nuclear factor κB (NF-κB) activator 1 (Act1) is an adaptor protein and E3 ubiquitin ligase that is critical for signaling by either IL-17 or IL-25, and it is recruited to their receptors (IL-17R and IL-25R) through heterotypic interactions between the SEFIR [SEF (similar expression to fibroblast growth factor genes) and IL-17R] domain of Act1 and that of the receptor. SEFIR domains have structural similarity with the Toll-IL-1 receptor (TIR) domains of Toll-like receptors and IL-1R. Whereas the BB' loop of TIR is required for TIR-TIR interactions, we found that deletion of the BB' loop from Act1 or IL-17RA (a common subunit of both IL-17R and IL-25R) did not affect Act1-IL-17RA interactions; rather, deletion of the CC' loop from Act1 or IL-17RA abolished the interaction between both proteins. Surface plasmon resonance measurements showed that a peptide corresponding to the CC' loop of Act1 bound directly to IL-17RA. A cell-permeable decoy peptide based on the CC' loop sequence inhibited IL-17- or IL-25-mediated signaling in vitro, as well as IL-17- and IL-25-induced pulmonary inflammation in mice. Together, these findings provide the molecular basis for the specificity of SEFIR-SEFIR versus TIR-TIR domain interactions and consequent signaling. Moreover, we suggest that the CC' loop motif of SEFIR domains is a promising target for therapeutic strategies against inflammatory diseases associated with IL-17 or IL-25 signaling.

Anti-CXCL5 therapy ameliorates IL-17-induced arthritis by decreasing joint vascularization.

IL-17-induced joint inflammation is associated with increased angiogenesis. However, the mechanism by which IL-17 mediates angiogenesis is undefined. Therefore, the pathologic role of CXCL1 and CXCL5 was investigated in arthritis mediated by local expression of IL-17, employing a neutralizing antibody to each chemokine. Next, endothelial chemotaxis was utilized to examine whether endothelial migration was differentially mediated by CXCL1 and CXCL5. Our results demonstrate that IL-17-mediated disease activity was not affected by anti-CXCL1 treatment alone. In contrast, mice receiving anti-CXCL5 demonstrated significantly reduced clinical signs of arthritis, compared to the mice treated with IgG control. Consistently, while inflammation, synovial lining thickness, bone erosion and vascularization were markedly reduced in both the anti-CXCL5 and combination anti-CXCL1 and 5 treatment groups, mice receiving anti-CXCL1 antibody had clinical scores similar to the control group. In contrast to joint FGF2 and VEGF levels, TNF-α was significantly reduced in mice receiving anti-CXCL5 or combination of anti-CXCL1 and 5 therapies compared to the control group. We found that, like IL-17, CXCL1-induced endothelial migration is mediated through activation of PI3K. In contrast, activation of NF-κB pathway was essential for endothelial chemotaxis induced by CXCL5. Although CXCL1 and CXCL5 can differentially mediate endothelial trafficking, blockade of CXCR2 can inhibit endothelial chemotaxis mediated by either of these chemokines. These results suggest that blockade of CXCL5 can modulate IL-17-induced inflammation in part by reducing joint blood vessel formation through a non-overlapping IL-17 mechanism.

Adverse functions of IL-17A in experimental sepsis.

IL-17A is a proinflammatory cytokine produced by a variety of cells. In the current study, we examined the role of IL-17A in sepsis induced in mice by cecal ligation and puncture (CLP). IL-17A levels, which rose time-dependently in plasma after CLP, were not affected in the absence of alphabeta T cells or neutrophils. In sharp contrast, gammadelta T cell-knockout or gammadelta T cell-depleted mice displayed baseline IL-17A plasma levels after CLP. Neutralization of IL-17A by two different antibodies improved sepsis (survival from approximately 10% to nearly 60%). Unexpectedly, antibody treatment was protective, even when administration of anti-IL-17A was delayed for up to 12 h after CLP. These protective effects of IL-17A blockade were associated with substantially reduced levels of bacteremia together with significant reductions of systemic proinflammatory cytokines and chemokines in plasma. In vitro incubation of mouse peritoneal macrophages with lipopolysaccharide (LPS) in the copresence of IL-17A substantially increased the production of TNF-alpha, IL-1beta, and IL-6 by these cells. These data suggest that, during experimental sepsis, gammadelta T cell-derived IL-17A promotes high levels of proinflammatory mediators and bacteremia, resulting in enhanced lethality. IL-17A may be a potential therapeutic target in sepsis.

Interleukin 17 synergises with tumour necrosis factor alpha to induce cartilage destruction in vitro.

BACKGROUND: Interleukin 17 (IL17) is produced by activated T cells and has been implicated in the development of bone lesions and cartilage degradation in rheumatoid arthritis (RA). OBJECTIVE: To determine whether IL17, alone or together with tumour necrosis factor alpha (TNFalpha), induces cartilage destruction in vitro. METHODS: Fetal mouse metatarsals stripped of endogenous osteoclast precursors were used to study the effect of IL17 on cartilage degradation independently of osteoclastic resorption. Cartilage destruction was analysed histologically by Alcian blue staining. RESULTS: IL17 alone, up to 100 ng/ml, had no effect on the cartilage of fetal mouse metatarsals. IL17 (>/=0.1 ng/ml), however, induced severe cartilage degradation when given together with TNFalpha (>/=1 ng/ml). The cytokine combination decreased Alcian blue staining, a marker of proteoglycans, throughout the metatarsals and induced loss of the proliferating and early hypertrophic chondrocyte zones. TNFalpha alone also decreased Alcian blue staining, but not as dramatically as the cytokine combination. In addition, it did not induce loss of chondrocyte zones. Treatment with inhibitors of matrix metalloproteinase (MMP) activity and nitric oxide synthesis showed that MMP activity played a part in cartilage degradation, whereas nitric oxide production did not. CONCLUSIONS: IL17, together with TNFalpha, induced cartilage degradation in fetal mouse metatarsals in vitro. IL17 may, therefore, participate in the development of cartilage destruction associated with RA by enhancing the effects of TNFalpha and may provide a potential therapeutic target.

Interleukin 17, a T-cell-derived cytokine, promotes tumorigenicity of human cervical tumors in nude mice.

Interleukin (IL) 17 is a proinflammatory cytokine secreted mainly by activated human memory CD4 T cells that induces IL-6, IL-8, and nitric oxide. Because IL-6 and IL-8 have been implicated in the pathogenesis of cervical cancer, we investigated the action of IL-17 on human cervical tumor cell lines in vitro and in vivo. We showed that in vitro, IL-17 increases IL-6 and IL-8 secretion by cervical carcinoma cell lines at both protein and mRNA levels. No direct effect of IL-17 on in vitro proliferation of cervical tumor cell lines could be demonstrated. However, two cervical cell lines transfected with a cDNA encoding IL-17 exhibited a significant increase in tumor size as compared to the parent tumor when transplanted in nude mice. This enhanced tumor growth elicited by IL-17 was associated with increased expression of IL-6 and macrophage recruitment at the tumor site. A potential role of IL-17 in modulation of the human cervical tumor phenotype was also supported by its expression on the cervical tumor in patients with CD4 infiltration. IL-17 therefore behaves like a T-cell-specific cytokine with paradoxical tumor-promoting activity. This may partially explain previous reports concerning the deleterious effect of CD4 T cells in cancer.