Ex vivo Immuno-modulatory effect of Echinococcus granulosus laminated layer during allergic rhinitis and allergic asthma: A study in Algerian Patients.

The effect of helminthic infections on allergic diseases and asthma is still inconclusive. Moreover, there is considerable evidence suggesting that nitric oxide (NO), metalloproteinases and pro-inflammatory cytokines play a significant role in the physiopathology of these diseases. In this sense, the aim of our study is to investigate the ex vivo immunomodulatory effect of the laminated layer (LL, outside layer of parasitic cyst) of the helminth Echinococcus granulosus on NO, IL-17A and IL-10 production. In the first step of our study, we evaluated in vivo the NO, MMP-9, IL-17A, IL-10 levels in Algerian patients with allergic asthma and allergic rhinitis and their changes in relation with exacerbation status of the patients. In the principal part of our work, we assessed NO, IL-10 and IL-17A levels in supernatants of patients PBMC cultures before and after stimulation with LL. Our results indicate a significant reduction in NO production by PBMC of patients with allergic rhinitis and allergic asthma whether mild, moderate or severe after stimulation with LL. Interestingly, LL induces a significant decrease in the production of NO and IL17-A levels as well as an increase in the production of IL-10 in the cultures performed with PBMC of patients with severe allergic asthma. Importantly, our data indicate that LL exert a down-modulatory effect on inflammatory mediators (NO, IL-17A) and up immune-regulatory effect on IL-10 production. Collectively, our study supports the hygiene hypothesis suggesting that Echinococcus granulosus infection like other helminths could prevent and/or modulate inflammation responses during inflammatory diseases.

Aberrant up-regulation of iNOS/NO system is correlated with an increased abundance of Foxp3+ cells and reduced effector/memory cell markers expression during colorectal cancer: immunomodulatory effects of cetuximab combined with chemotherapy.

Colorectal cancer (CRC) remains the most cancer type related to chronic inflammation; however, the mechanisms that link inflammation to CRC development and progression are still poorly understood. Our study aimed to investigate one of the prominent inflammatory response in cancers, iNOS/NO system. In this regard, we evaluated the link between the iNOS/NO system and CRC progression, its relation with the host immune responses and its response to cetuximab combined with chemotherapy. We found that the nitrite levels were nearly twice as high in metastatic CRC plasma and culture supernatants from PBMCs and tumor explants compared with those without metastases and healthy controls. Interestingly, we showed that the highest iNOS expression and NO levels are present in the damaged CRC tissues that have highest leukocyte infiltration. Our findings highlight the implication of iNOS/NO system in tissue alteration and leukocyte invasion. Thus, we observed imbalance between effector/memory T cell markers and Treg transcription factor (Foxp3). Accordingly, we detected higher IFNγ and T-bet expression levels in colorectal tumor tissues at early stage. In contrast, consistent with iNOS and Foxp3 expression, TGFß, CTLA-4 and IL-10 were significantly related to the tumor stage progression. Furthermore, our study revealed that Cetuximab combined with chemotherapy treatment markedly down-regulates iNOS/NO system as well as IL-10 and TGFß levels. Altogether, we conclude that cetuximab can potentiate the efficacy of chemotherapy, particularly by iNOS/NO system and immunosuppressive cytokines modulation. Thus, we suggest that iNOS/NO system may represent an attractive candidate biomarker for monitoring CRC progression, malignity and response to therapy.

All-Trans Retinoic Acid Modulates TLR4/NF-κB Signaling Pathway Targeting TNF-α and Nitric Oxide Synthase 2 Expression in Colonic Mucosa during Ulcerative Colitis and Colitis Associated Cancer.

Colitis associated cancer (CAC) is the colorectal cancer (CRC) subtype that is associated with bowel disease such as ulcerative colitis (UC). The data on role of NF-κB signaling in development and progression of CAC were derived from preclinical studies, whereas data from human are rare. The aim of this work was to study the contribution of NF-κB pathway during UC and CAC, as well as the immunomodulatory effect of all-trans retinoic acid (AtRA). We analyzed the expression of NOS2, TNF-α, TLR4, and NF-κB, in colonic mucosa. We also studied NO/TNF-α modulation by LPS in colonic mucosa pretreated with AtRA. A marked increase in TLR4, NF-κB, TNF-α, and NOS2 expression was reported in colonic mucosa. The relationship between LPS/TLR4 and TNF-α/NO production, as well as the role of NF-κB signaling, was confirmed by ex vivo experiments and the role of LPS/TLR4 in NOS2/TNF-α induction through NF-κB pathway was suggested. AtRA downregulates NOS2 and TNF-α expression. Collectively, our study indicates that AtRA modulates in situ LPS/TLR4/NF-κB signaling pathway targeting NOS2 and TNF-α expression. Therefore, we suggest that AtRA has a potential value in new strategies to improve the current therapy, as well as in the clinical prevention of CAC development and progression.