Browsing by Subject "cytokines"
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Item Cellular Mechanisms in the Ocular Actions of Endothelin(1996-12-01) White, Karen A.; Yorio, Thomas; Pang, Iok-Hou; Dobbs, RichardWhite, Karen A., Cellular Mechanisms in the Ocular Actions of Endothelin. Doctor of Philosophy (Biomedical Sciences/Pharmacology), December, 1996, 151 pp., 25 tables, 23 figures, references, 111 titles. Endothelins are a family of regulatory peptides which could have important implications in this regulation of aqueous humor outflow and intraocular pressure (IOP). The objectives of this dissertation were to investigate the cellular mechanism of endothelin (ET) receptor interactions in ocular tissues focusing on their effect on second messengers such as phospholipase C (PLC) and calcium, and their interactions with phospholipase A2 (PLA2) in ciliary muscle cells. The hypothesis was that in human ciliary muscle (HCM) cells, endothelin-1 (ET-1), via the ETA receptor and a pertussis toxin sensitive G-protein, activates PLC, which in turn stimulates calcium mobilization. Independent of this pathway, ET-1 also activates PLA2 and increases the release of prostaglandins. These two pathways provide a cellular second messenger balance that influences ciliary smooth muscle contraction. The current study demonstrated that ET-1 and endothelin-2 (ET-2) stimulate calcium mobilization in HCM cells via an ETA receptor subtype. It appears that the increase in intracellular calcium ([Ca2+]i) is the result of ET coupled to PLC via a pertussis toxin sensitive G-protein. A biphasic calcium response is elicited with ET stimulation consisting of a transient increase in [Ca2+]I which appears to be primarily due to release of intracellular stores, followed by a lower sustained phase which appears to be dependent on the influx of extracellular calcium. Endothelin-1 also appears to stimulate an increase in prostaglandin E2 (PGE2) formation through activation of PLA2. Furthermore, it appears that the effects of ET-1 on PLC and calcium are independent of the ET-1 effects on PGE2 production, such that the ET-1 induced increase in [Ca2+]I are coupled to the PLC signaling pathway, whereas increase in PGE2 production appears to be the result of an ETA receptor coupled PLA2. Whether there are different subtypes of ETA receptors or the receptor is coupled through different G-proteins is uncertain. Endothelin-1 and Big ET-1 immunoreactivity was also observed in both HCM and human nonpigmented ciliary epithelial (HNPE) cells. This is the first time that ET-1 and Big ET-1 immunoreactivity has been detected in the HCM cells, suggesting that these cells have the capability to synthesize both peptides. Furthermore, the increase in ET-1 and Big ET-1 immunoreactivity upon stimulation with TNF-α suggests that cytokines may be important regulators of ET synthesis and release. The findings of this research aid in the understanding of the mechanism of action whereby ETs regulate aqueous humor dynamics and IOP. Through a better understanding of the cellular actions of ET, insight is gained into the development of new ocular selective agents acting at the ET receptor.Item For Better or for Worse: The Influence of NK Cells, IFN-y and IL-4 on the Development of Protective Adaptive Immunity in Mycoplasma Respiratory Disease(2008-08-01) Bodhankar, Sheetal; Porunelloor A. Mathew; Stephen R. Grant; Rance E. BergSheetal Bodhankar, For better or for worse: The influence of NK cells, IFN-y and IL-4 on the generation of protective adaptive immunity in mycoplasma respiratory disease, Doctor of Philosophy (Microbiology and Immunology) August 2008, 136 pp., 13 illustrations, 3 tables, bibliography, 176 titles. The purpose of these studies was to evaluate the contribution of NK cells and the polarizing cytokines, IFN-y and IL-4, in the generation of protective adaptive immunity against mycoplasma infection. Presence of NK cells during the generation of adaptive immunity resulted in detrimental immune responses. However, upon depletion of NK cells, prior to nasal-pulmonary immunizations, mice demonstrated better clearance of mycoplasma from the respiratory tracts. That the NK cells hindered with the beneficial development of adaptive immune responses via lymphoid cells was demonstrated, since no protection was demonstrated in SCID mice. Furthermore, purified pulmonary T and B lymphocytes primed in a NK cell depleted environment as opposed to one’s primed in a versus non-depleted environment could transfer protection to naïve mice. Interestingly, this is the first time that a favorable role of functional CD4 T cells in mediating protection in mycoplasma respiratory disease was demonstrated. The presence of NK cells at the time of nasal-pulmonary immunization also modulated mycoplasma-specific IFN-y and IL-4 responses in lungs and lower respiratory nodes. In evaluating the roles of IFN-y and IL-4, it was demonstrated that the absence of a single cytokine alters a vast array of chemokines and cytokines produced in response to mycoplasma infection. Corresponding to the higher numbers of mycoplasma and severity in disease due to the loss of IFN-y, altered cytokine and chemokine responses in the lungs to mycoplasma infection were demonstrated. Nasal-pulmonary immunization of IFN-y mice exacerbated, rather than reduced, mycoplasma disease and infection, whereas immunization of IL-4 mice significantly enhanced protection along the respiratory tract particularly in the lungs. Prominent Th-2 type immune responses in the lungs of IFN-y mice corresponded to the severe immunopathologic reactions developed after mycoplasma infection and immunization. These studies demonstrated diverse but crucial functions for NK cells, IFN-y and IL-4 vital towards the development of protective adaptive immune responses against mycoplasma respiratory infection that will have a significant impact on future studies on respiratory immunology.Item Lipopolysaccharide Challenge Reveals Hypothalamic-Pituitary-Adrenal Axis Dysfunction in Murine Systemic Lupus Erythematosus(MDPI, 2018-10-04) Pham, Grace S.; Mathis, Keisa W.Crosstalk between the brain and innate immune system may be dysregulated in systemic lupus erythematosus (SLE), a chronic autoimmune disease that presents with dysautonomia and aberrant inflammation. The hypothalamic-pituitary-adrenal (HPA) axis is an endogenous neuro-endocrine-immune pathway that can regulate inflammation following activation of vagal afferents. We hypothesized that chronic inflammatory processes in SLE are in part due to HPA axis dysfunction, at the level of either the afferent vagal-paraventricular nuclei (PVN) interface, the anterior pituitary, and/or at the adrenal glands. To study this, we challenged female control and SLE mice with lipopolysaccharide (LPS) and measured c-Fos expression as an index of neuronal activation, plasma adrenocorticotrophic hormone (ACTH) as an index of anterior pituitary function, and plasma corticosterone as an index of adrenal function. We found that c-Fos expression in the PVN, and plasma ACTH and corticosterone were comparable between unchallenged SLE and control mice. PVN c-Fos was increased similarly in control and SLE mice three hours after LPS challenge; however, there were no changes in plasma ACTH amongst any experimental groups post inflammatory challenge. Plasma corticosterone was markedly increased in LPS-challenged SLE mice compared to their vehicle-treated counterparts, but not in controls. Paradoxically, following LPS challenge, brain and spleen TNF-alpha were elevated in LPS-challenged SLE mice despite heightened plasma corticosterone. This suggests that, despite normal c-Fos expression in the PVN and activation of the HPA axis following LPS challenge, this cumulative response may not adequately defend SLE mice against inflammatory stimuli, leading to abnormally heightened innate immune responses and peripheral inflammation.Item The Many Faces of Innate Immunity in SARS-CoV-2 Infection(MDPI, 2021-06-04) Hanan, Nicholas; Doud, Ronnie L., Jr.; Park, In-Woo; Jones, Harlan P.; Mathew, Stephen O.The innate immune system is important for initial antiviral response. SARS-CoV-2 can result in overactivity or suppression of the innate immune system. A dysregulated immune response is associated with poor outcomes; with patients having significant Neutrophil-to-Lymphocyte ratios (NLR) due to neutrophilia alongside lymphopenia. Elevated interleukin (IL)-6 and IL-8 leads to overactivity and is a prominent feature of severe COVID-19 patients. IL-6 can result in lymphopenia; where COVID-19 patients typically have significantly altered lymphocyte subsets. IL-8 attracts neutrophils; which may play a significant role in lung tissue damage with the formation of neutrophil extracellular traps leading to cytokine storm or acute respiratory distress syndrome. Several factors like pre-existing co-morbidities, genetic risks, viral pathogenicity, and therapeutic efficacy act as important modifiers of SARS-CoV-2 risks for disease through an interplay with innate host inflammatory responses. In this review, we discuss the role of the innate immune system at play with other important modifiers in SARS-CoV-2 infection.Item The Prognostic Value of Serum Cytokines in Patients with Acute Ischemic Stroke(JKL International, 2019-06-01) Li, Xianmei; Lin, Siyang; Chen, Xiaoli; Huang, Wensi; Li, Qian; Zhang, Hongxia; Chen, Xudong; Yang, Shaohua; Jin, Kunlin; Shao, BeiThe inflammatory response is an unavoidable process and contributes to the destruction of cerebral tissue during the acute ischemic stroke (AIS) phase and has not been addressed fully to date. Insightful understanding of correlation of inflammatory mediators and stroke outcome may provide new biomarkers or therapeutic approaches for ischemic stroke. Here, we prospectively recruited 180 first-ever AIS patients within 72 hrs after stroke onset. We used the National Institutes of Health Stroke Scale (NIHSS) to quantify stroke severity and modified Rankin scale (mRS) to assess the 3-month outcome for AIS patients. Initially, we screened 35 cytokines, chemokines, and growth factors in sera from 75 AIS patients and control subjects. Cytokines that were of interest were further investigated in the 180 AIS patients and 14 heathy controls. We found that IL-1RA, IL-1beta, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-13, IL-15, EGF, G-CSF, Flt-3L, GM-CSF and Fractalkine levels were significantly decreased in severe stroke patients. In particular, IL-1beta, IL-4, IL-5, IL-7, IL-9, IL-10, IL-15, G-CSF and GM-CSF were significantly reduced in AIS patients with poor outcome, compared to those with good prognosis. IL-6 was notably higher in the poor outcome group. Only IL-9 level decreased in the large infarct volume group. After adjusting for confounders, we found that IL-5 was an independent protective factor for prognosis in AIS patients with an adjusted OR of 0.042 (P = 0.007), whereas IL-6 was an independent risk predictor for AIS patients with an adjusted OR of 1.293 (P = 0.003). Our study suggests the levels of serum cytokines are related to stroke severity, short-term prognosis and cerebral infarct volume in AIS patients.