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AhR is also known to cross talk
AhR is also known to “cross-talk” with a variety of other cell signaling pathways, which has been the focus of a number of recent reviews [40], [41], [42]. It has long been known that TCDD is anti-estrogenic. For example, activation of AhR by TCDD and related HAHs inhibits estrogen dependent uterus development. In addition, activation of AhR upregulates the expression of key cytochrome P450 genes (e.g. Cyp1a1, Cyp1a2 and Cyp1b1) that promote the clearance of 17β-estradiol (E2) and estrone (E1), two predominant ligands of the estrogen receptor (ER) [43]. Activated AhR can also function as a ubiquitin ligase that degrades ER via the proteasome in breast cancer cells [44], or titrates down the cellular pool of common transcription cofactors required for ER function [45]. Conversely, AhR may also be pro-estrogenic in some contexts. Activation of AhR by ligands upregulates Cyp19a1 gene expression, which encodes enzyme aromatase that is essential for estrogen biosynthesis [35]. Ligand activated AhR has also been shown to function as a transcriptional co-activator of ER that potentiates estrogen responsive gene expression even in the absence of ER ligand [46].
In addition to ER, AhR is also known to interact with the RelA subunit of NF-κB (nuclear factor-kappa B). Interaction between AhR and NF-κB upregulates c-myc gene expression and promotes mammary cell proliferation and tumorigenesis [47]. On the other hand, TCDD dependent AhR/Rb (retinoblastoma) interaction results in entospletinib arrest at G1 phase.
Crosstalk between AhR and other cell signaling pathways could also occur indirectly via dissociation of the cytosolic AhR complex. The AhR chaperone complex has also been reported to associate with Cdc37 and the non-receptor tyrosine kinase Src (Fig. 1). Interaction between AhR and ligand leads to the dissociation of Src . AhR free Src is then translocated into cell membrane, where it phosphorylates EGFR (epidermal growth factor receptor) and modulates ERK1/2 target gene expression via the MAPK (mitogen-activated protein kinase) signaling cascade [48].
Finally, a permanent role of AhR in T cell development and immunity has also been reported [49]. Over the last decade, there has been an explosion of scientific research that connects AhR with immune responses, providing further examples of physiological functions of AhR independent of adaptive xenobiotic metabolism. For the rest of this commentary, we will focus on recent advances relating various AhR pathways to immune responses, with a special emphasis on the molecular details from AhR activation to immunomodulation.
AhR and immunity
Numerous studies have pointed to a role of AhR in immunomodulation (Fig. 2). Exposure of laboratory animals to TCDD leads to profound immunosuppression. For example, activation of AhR by its classical ligand TCDD suppresses experimental autoimmune encephalomyelitis (EAE) [50], experimental autoimmune uveoretinitis (EAU) [51], and inflammatory response in TNBS (2,4,6-trinitrobenzenesulfonic acid) treated mice [52], which model human Crohn's disease. Treatment of TCDD also reduces Type 1 diabetes in the non-obese diabetic mouse [53], and attenuates the severity of allergy responses in atopic dermatitis, peanut allergy and house dust mite induced asthma in rodents [54], [55], [56].
In addition to the severe immunosuppression, TCDD-exposed mice also exhibit signs of thymic involution and increased susceptibility to viral infection [57]. Both of these effects are AhR dependent, as AhR null mice are completely protected against TCDD induced immune toxicity [58]. Conversely, transgenic mice expressing a constitutively active form of AhR under the control of a T cell specific promoter recapitulates the thymic defect seen in TCDD-exposed mice [59], [60].
As the thymus is the major organ for T cell development, and age related thymus atrophy is a major cause behind increased susceptibility to infection in the elderly, a detailed understanding of the mechanisms underlying TCDD induced thymus involution has generated considerable interest. Studies by Laiosa et al. suggested that persistent AhR activation reduces T-lymphocyte numbers in the thymus via reduced thymocyte proliferation [61] and impaired thymus seeding by bone marrow-derived prethymic stem cells [62]. Furthermore, premature migration of CD4/CD8 double-negative progenitor T-cells from the thymus to peripheral lymphoid organs [63], and AhR dependent induction of thymopoeisis inhibition factor Klf2 (Kruppel-like factor 2) in developing thymocytes [64], could also contribute to the observed severe thymus atrophy seen in TCDD-exposed mice.