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Histamine Releasing Factor-Therapeutic Target For Asthma

BY: Hareepriyaw M | Category: Biotech-Research | Submitted: 2014-01-10 10:48:26
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Article Summary: "Translationally controlled tumor protein or TCTP is otherwise called as a histamine releasing factor (HRF). The basophils taken from allergic donors were releasing histamine induced by lavages of nose and bronchoalveoli, and skin blister fluids. These donors were called as HRF responders while those people having basophils not r.."


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Introduction

Translationally controlled tumor protein or TCTP is otherwise called as a histamine releasing factor (HRF). The basophils taken from allergic donors were releasing histamine induced by lavages of nose and bronchoalveoli, and skin blister fluids. These donors were called as HRF responders while those people having basophils not responding to histamine releasing factors are called as HRF non-responders. HRF is expressed everywhere and is an intracellular protein. The association between HRF and elongation factor-1 delta or eElongation factor 1B-beta was identified by certain research groups. Hence, HRF was found to possess an important role in the cell involving with the elongation step of protein synthesis.

Cellular interactions of HRF

The histamine releasing factor is present in the intracellular pool and is considered to be associated with secretory processes and vesicular trafficking. HRF is also found to be associated with a tumor suppressor activated pathway-6. TCTP or HRF was known to cause inflammation in mice with asthma and allergy. According to a research study, HRF is a dimer attached to the subsets of IgG and IgE antibodies at the N-terminus region as well as at the Fab internal regions in the immunoglobulins of mouse mast cells. HRF is found to block the production of cytokines from the Jurkat T cell line and primary T cells. It modulates the cytokine secretion from basophils, T cells and eosinophils of humans.

Intracellular functions of HRF

Transcription and post transcriptional activities of HRF are controlled by calcium. HRF is a tubulin binding protein and is found to be associated with microtubules in the cell cycle. It was found to be associated with different cancers like breast, colon and prostate cancers. Another study revealed that the role of HRF in the development of tumor might be concerned with its own anti-apoptotic activity. It was recently reported that HRF enhances the degradation of p53 and p53 was found to suppress the transcription of HRF.

Generating inducible HRF transgenic mouse

HRF/TCTP was targeted to the Clara cells of lung epithelium and was expressed using CC10 promoter. Its expression is done in the process of generating transgenic mice with tetracycline response element-HRF enhanced green fluorescent protein (EGFP). The ribosome entry 2 site expressed EGFP gene as a reporter protein accompanied by HRF, so that the expression of transgenic human HRF is recognized. The transgenic construct was regulated by doxycycline and tetracycline. The production of IL-4 by human basophils is stimulated by HRF/TCTP. The firm adhesion property of basophils is aided by beta-1 integrin. The expression of vascular cell adhesion molecule, which is the ligand for beta-1 integrin is triggered by IL-4 and the vascular cell adhesion molecule is found to be vital for migration of eosinophils. Therefore, IL-4 production in the basophils explains the increase in asthma and allergy after the increased production of HRF.

Priming response of HRF and its effect on SHIP-1

A research study showed a negative relationship of SHIP-1 and phosphatase with the HRF/TCTP mediated histamine release from basophils. The variation in the SHIP-1 levels was also acknowledged in patients suffering from chronic idiopathic urticaria. In this disease condition, SHIP-1 levels were increased and the histamine release induced by anti-IgE was decreased. The levels of SHIP-1 will be altered in some of the diseased states of the human beings. A substance called LY294002 was known to inhibit PI3 kinase, which was also found to inhibit the release of histamine from basophils by HRF. Many of the vital functions of basophils are controlled by PI3 kinase activity and SHIP-1 is found to be responsible for blocking the activity of PI3 kinase by eliminating the 5' phosphatase from PIP3. So, SHIP-1 is considered as a major controller of all these reactions. The mouse mast cells knocked out with SHIP-1 could express more amount of PIP3, which will send constant calcium signals that might cause degranulation.

HRF intracellular signaling

Intracellular signal transduction events in the basophils were activated successfully by HRF only in the people who are considered as responders of HRF/TCTP in releasing histamine. When anti-IgE was used for stimulating the basophils in HRF/TCTP donors, there was an increase in the metabolite called leukotriene C4.

Clinical significance of HRF

Some studies have reported the influence of immunotherapy on HRF production. The allergic rhinitis patients without asthma given with immunotherapy, improved the symptoms and prevented the production of HRF from peripheral blood mononuclear cells. The children with atopic dermatitis and food allergy had their basophils releasing histamine and the mononuclear cells taken from them produced HRF/TCTP. HRF/TCTP can be shown as therapeutic target when the binding of HRF to its receptor is blocked. The antibody that blocks HRF/TCTP was found to be beneficial in this method of proving the therapeutic efficacy of HRF. The binding sequences of mHRF to IgE and IgG molecules explain the extracellular activities of HRF/TCTP. The HRF regions important for binding to the immunoglobulins are 19-residue peptide of the N - terminal region and 107-135 residues of H3 region.

Reference:

Susan M MacDonald. The potential role of histamine releasing factor (HRF) as a therapeutic target for treating asthma and allergy. Journal of Asthma and Allergy 2012:5, 51-59.


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