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Herpesvirus microRNAs for Use in Gene Therapy Immune-Evasion Strategies
Published in Yashwant Pathak, Gene Delivery, 2022
Vineet Mahajan, Shruti Saptarshi, Yashwant Pathak
miR-K12-5 was demonstrated to mitigate both mRNA and protein expression of MYD88, a cytosolic protein involved in toll like receptor/IL-1R signaling that is central to the innate and adaptive immune response arms. KSHV miR-K1 enhances the NF-κB pathway activity by directly targeting the key component IκB to inhibit viral lytic replication. Furthermore, KSHV v-miRNAs reduce expression of C/EBPβ p20 (LIP), a known negative regulator of IL6 and IL10 cytokines, to regulate the cytokine signaling in infected cells.1 KSHV miRNAs (miR-K12-1, miR-K12-3-3p, miR-K12-6-3p, and miR-K12-11) have also been shown to influence the cell cycle regulation of the host in order to indirectly promote viral pathogenesis by acting on key genes such as p21, p53, and Thrombospondin 1 (THBS1) involved in cell cycle progression.13
Non-Hodgkin Lymphoma
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Piers Blombery, David C. Linch
Like other lymphomas of immune-privileged sites, PCNSL has a relatively high incidence of MYD88/CD79B mutations.54 This observation has led to the investigation of BTK inhibitors such as ibrutinib in this condition which have shown promising efficacy in initial trials.58
Waldenström Macroglobulinemia
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The discovery of the recurrent somatic mutation of the MYD88 gene resulting in the change of the amino acid leucine to proline at position 265 (L265P) contributed to the understanding of WM [27]. The MYD88 adaptor protein is part of the TLR and interleukin-1 receptor (IL-1R) signaling pathway [27]. This “gain-of-function” MYD88L265P mutation promotes cell growth and survival through transcription of nuclear factor kappa-light-chain of activated B cells (NF-κB), one of the final products of the TLR and IL-1 pathways (Figure 82.1) [28]. MYD88L265P mutation has been detected in 70%–90% of sporadic WM cases and in all familial WM cases [27,29,30]; however, no evidence for the presence of a germ-line MYD88 mutation exists in cases of familial WM [31]. The MYD88L265P has also been described in patients with IgM MGUS (87%) and in a small proportion of patients with splenic marginal zone lymphoma (4%), mucosa-associated lymphoid tissue lymphoma (7%), and rarely in CLL [29,32]. The role of the MYD88L265P mutation in the pathogenesis of WM is still unclear; it could represent a driver mutation for the progression of IgM MGUS to WM or merely an early event in this disease [19,27].
Zanubrutinib for the treatment of Waldenström Macroglobulinemia
Published in Expert Review of Hematology, 2020
Kenneth J. C. Lim, Constantine S. Tam
Recent studies have helped shed further light on the pathogenesis of WM through the molecular examination of acquired genetic mutations associated with WM. The identified MYD88 gene was found to encode an adaptor protein involved in Toll-like receptor and interleukin-1 receptor signaling. When these receptors are activated, the MYD88 protein undergoes homodimerization and activates downstream signaling pathways involving the phosphorylation of interleukin-1 receptor-associated kinases (IRAK1 and IRAK 4) followed by IκBα and ultimately the activation of the pro-survival nuclear factor κB (NF-κB) pathway. L265P is a gain in function mutation found in >90% of WM cases. The L265P mutation allows for spontaneous, independent MYD88 homodimerization and subsequent constitutive activation of NF-κB [2,3]. The second gene of interest in WM is the CXCR4 gene with mutations found in approximately 30% of WM cases. These mutations include frameshift and nonsense mutations of CXCR4 similar to those seen in germline mutations associated with the rare congenital immune deficiency condition WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome. Stimulation of CXCR4 by its ligand CXCL12 stimulates WM cell migration, adhesion, and homing. These WHIM-like mutations of CXCR4WHIM promote prolonged activation of CXCR4 by preventing receptor internalization which prolongs CXCR4 stimulation by CXCL12. This promotes the survival, growth, and dissemination of WM cells [4,5]. The presence of these mutations has prognostic implications to therapy and form the basis of current targeted approaches.
Enterobactin induces the chemokine, interleukin-8, from intestinal epithelia by chelating intracellular iron
Published in Gut Microbes, 2020
Piu Saha, Beng San Yeoh, Xia Xiao, Rachel M. Golonka, Ahmed A. Abokor, Camilla F. Wenceslau, Yatrik M. Shah, Bina Joe, Matam Vijay-Kumar
Besides the superior kinetics of Ent, we envisaged that Ent mediated IL-8 secretion might be dependent on N-formyl peptide receptors (FPRs). FPRs are broadly expressed pattern recognition receptors, which can bind and induce responses to bacteria-derived peptides and amino acid derivatives.43,60 We considered the possibility that Ent could interact with FPRs given that the cyclic structure of Ent contains a tri-ester lactone of 2,3-dihydroxybenzoylserine, which is formed by an amide linkage of three 2,3-dihydroxybenzoic acid groups to three L-serine units.47 Our results indicate that Ent mediated IL-8 secretion may be FPR dependent as this response can be inhibited by Boc2, a widely used antagonist of FPRs, as well as by cyclosporine H, which is a selective inhibitor of FPR1. Though the possibility that Ent can activate FPR is worth considering, it is also plausible that inhibiting FPR via pharmacological inhibitors could induce a state of immune tolerance that dampens IECs IL-8 response to Ent. Aside from that, we also noted a lack of IL-8 response from MyD88 deficient colon cultures that were treated with Ent ex vivo. MyD88 is known to be a key adaptor protein that relays inflammatory signals and subsequent induction of cytokines including chemokines such as IL-8.61 We infer the possibility that the Ent-IL-8 axis may putatively signal through an inflammatory pathway upstream of MyD88. However, the exact role of FPR and MyD88 and how their pathways intersect within the Ent-IL-8 axis remains poorly understood and would certainly require further studies and validation.
Role of inflammation in the malignant transformation of pleural mesothelial cells induced by multi-walled carbon nanotubes
Published in Nanotoxicology, 2020
Xiaopei Huang, Yijun Tian, Wenjing Shi, Jikuai Chen, Lang Yan, Lijun Ren, Xiaofang Zhang, Jiangbo Zhu
We observed that low-dose and long-term exposure of MWCNTs can trigger the malignant transformation of Met 5A cells, consistent with the results of Lohcharoenkal et al. (2013), but the specific mechanism requires further study. In order to solve the above problem, we analyzed differentially expressed genes and screened the main molecular pathways that may participate in MWCNT-induced malignant transformation of Met 5A cells via GO and KEGG. The results signified that cytokine–cytokine receptor interaction, several signaling pathways (TNF, NF-κB, PI3K-Akt, and chemokine), and Nod-like and Toll-like receptor pathways played important roles in the transformation of mesothelial cells. NOD-like receptor is a pattern recognition receptor, of which NOD1 and NOD2 can activate NF-κB and mediate an inflammatory response (Cui et al. 2014). MyD88 is a key molecule in the Toll-like receptor signal transduction pathway and may activate NF-κB through a series of pathways (Li, Ogino, and Qian 2014). TNF is a class of cytokines that possess a variety of biological effects. As a member of the TNF family, TNF-α can activate the NF-κB signaling pathway and exert its cytotoxic and immune regulatory functions (Ben-Baruch 2019). In the PI3K-Akt signaling pathway, activated Akt may stimulate NF-κB (Aggarwal et al. 2019). Therefore, the NF-κB signaling pathway may be activated through multiple enriched pathways in cancer development.