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By Jamshed Arslan, Pharm. D., PhD.
The cellular pathway comprising tyrosine kinase Janus Kinase (JAK) and the transcription factor STAT connect extracellular signals from various cytokines, hormones and growth factors with the nuclear transcription machinery. Four JAK proteins (JAK1, JAK2, JAK3, TYK2) and seven STAT members (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6) have been identified in mammals. STAT proteins regulate the expression of numerous genes, including those related to cell survival, development, differentiation, migration, apoptosis, and immune response.
STAT6 was initially identified as IL-4Stat, but now we know that IL13 is also a prime activator of STAT6. The physiological functions associated with these two cytokines (IL4 and IL13) are deficient in STAT6 knockout mice. For example, STAT6 deficient mice have defunct Th2 helper T cell differentiation, an IL4-dependent processes. However, blocked differentiation of Th2 cells in STAT6-null mice is less pronounced than in IL4 deficient animals. The reason is that STAT6 transduces and integrates messages from both IL4 and IL13, and also induces the expression of GATA3, a master regulator of Th2 cells. Interestingly, unlike the development of Th2 cells , Th1 cells can develop independent of STAT6.
STAT6 is a well-established player in allergic inflammatory diseases. Many chemokines like CCL11, CCL17, CCL22, and CCL26 are implicated in allergic inflammation and these are all regulated in a STAT6-dependent manner. Mice that overexpress STAT6 or IL4 develop spontaneous allergic inflammation. On the other hand, B cells from STAT6 deficient mice fail to produce IgE against allergens and worms/helminths and therefore cannot expel helminth parasites.
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Immunocytochemical staining of phosphorylated STAT6 (Y641) using Rabbit Anti-Human Phospho-STAT6 (Y641) Monoclonal Antibody (MAB3717) in immersion fixed Daudi human Burkitt's lymphoma cell line. Cells were untreated (bottom) or treated with Recombinant Human IL-4 (204-IL; top). Cells were stained using the NorthernLights™ 557-conjugated Anti-Rabbit IgG Secondary Antibody (red; NL004) and counterstained with DAPI (NBP2-31156) (blue). |
Besides being a regulator of Th2 immunity, aberrant STAT6 is implicated in cancer and autoimmune diseases. STAT6 induces an immunosuppressive tumor microenvironment (TME) leading to tumor growth. Strong and diffuse nuclear staining for STAT6 is a commonly used diagnostic marker for solitary fibrous tumor. Non-hematopoietic STAT6 is a promising therapeutic target against inflammation (such as inflammatory bowel disease) and tumorigenesis.
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Immunohistochemical staining of Enolase 2 with Human/Mouse Enolase 2 Antigen Affinity-purified Polyclonal Antibody (AF5169) in immersion fixed paraffin-embedded sections of human brain (cortex). Tissue was stained using the Anti-Sheep HRP-DAB Cell & Tissue Staining Kit (brown; CTS019) and counterstained with hematoxylin (blue). |
A team of researchers in Germany were intrigued by the role of ethanol intoxication in the pathology of traumatic brain injury (TBI), such as those resulting from car crashes by drunk drivers (Heuvel et al., 2019 ). Using mice as a model system, they showed that ethanol intoxication can downregulate certain TBI-related inflammatory cytokines like TNF-α, where STAT6 acts as a critical mediator of this process. Ethanol intoxication induced phosphorylation of STAT6 in certain brain regions and the consequent transcription of STAT6-mediated genes was higher in treated mice relative to control mice. By using a brain-permeable STAT6 inhibitor, the team not only blocked ethanol’s beneficial effects on behavioral performance, but also the anti-inflammatory actions of ethanol on glial activation and cytokine production. In other words, STAT6 pathways plays a beneficial role in the ethanol-mediated immunomodulatory effects during TBI.
Jamshed Arslan, Pharm D, PhD
Dr Arslan is an Assistant Professor at Barrett Hodgson University, Pakistan,
where he uses various pedagogical methods to teach Pharm D students.
Research in focus
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Im, J. H., Yeo, I. J., Park, P. H., Choi, D. Y., Han, S. B., Yun, J., & Hong, J. T. (2020). Deletion of Chitinase-3-like 1 accelerates stroke development through enhancement of Neuroinflammation by STAT6-dependent M2 microglial inactivation in Chitinase-3-like 1 knockout mice. Experimental Neurology. https://doi.org/10.1016/j.expneurol.2019.113082
Kang, R., Zhu, S., Zeh, H., & Tang, D. (2018). The STING-STAT6 pathway drives Cas9-induced host response in human monocytes. Biochemical and Biophysical Research Communications. https://doi.org/10.1016/j.bbrc.2018.10.080
Lin, Y., Li, B., Yang, X., Liu, T., Shi, T., Deng, B., … He, R. (2019). Non-hematopoietic STAT6 induces epithelial tight junction dysfunction and promotes intestinal inflammation and tumorigenesis. Mucosal Immunology. https://doi.org/10.1038/s41385-019-0204-y
Mariño-Enríquez, Adrián & Jason L. Hornick (2019). Spindle Cell Tumors of Adults. Ed. Jason L. Hornick, In Practical Soft Tissue Pathology: A Diagnostic Approach, 2nd edition, pp. 15–100. https://doi.org/10.1016/B978-0-323-49714-5.00003-X.
olde Heuvel, F., Holl, S., Chandrasekar, A., Li, Z., Wang, Y., Rehman, R., … Roselli, F. (2019). STAT6 mediates the effect of ethanol on neuroinflammatory response in TBI. Brain, Behavior, and Immunity. https://doi.org/10.1016/j.bbi.2019.06.019
Recio, C., Guerra, B., Guerra-Rodríguez, M., Aranda-Tavío, H., Martín-Rodríguez, P., de Mirecki-Garrido, M., … Fernández-Pérez, L. (2019). Signal transducer and activator of transcription (STAT)-5: an opportunity for drug development in oncohematology. Oncogene. https://doi.org/10.1038/s41388-019-0752-3
Shaheen, Montaser & Hal E. Broxmeyer (2018). Cytokine/Receptor Families and Signal Transduction. Eds. Hoffman, Ronald et al., In Hematology, 7th edition, pp. 163–175. https://doi.org/10.1016/C2013-0-23355-9.
Sławińska, M., Lakomy, J., Biernat, W., Sokołowska-Wojdyło, M., Karczewska, J., Zabłotna, M., … Sobjanek, M. (2020). STAT3, STAT5A, STAT5B and STAT6 proteins are overexpressed in human basal cell carcinoma. Clinical and Experimental Dermatology. https://doi.org/10.1111/ced.14048
Song, Li & Christian Schindler (2010). JAK-STAT Signaling. Eds. Ralph A. Bradshaw and Edward A. Dennis. In Handbook of Cell Signaling, 2nd edition, pp. 2041–2048. https://doi.org/10.1016/B978-0-12-374145-5.00249-7.
