1Faculty of Medical Science and Research, Sai Nath University, Ranchi, Jharkhand-83519, India
2Department of Pharmacy, Shubham University, Bhopal, Madhya Pradesh-462010, India
Fever represents a complex physiological response orchestrated by multiple cellular and molecular mechanisms within the immune system. This comprehensive review examines the intricate relationships between antigen-induced mast cell activation, histamine release, and cyclooxygenase (COX) enzyme activity in fever pathogenesis. Mast cells, strategically positioned throughout tissues, serve as sentinel cells that respond to antigenic stimuli through rapid degranulation and mediator release. The subsequent cascade involves histamine-mediated vascular changes and the activation of COX enzymes, particularly COX-2, leading to prostaglandin E2 (PGE2) synthesis and hypothalamic thermoregulatory responses. Current evidence demonstrates that these pathways are interconnected through complex feedback mechanisms involving inflammatory cytokines, complement activation, and neuroimmune signalling. Understanding these molecular interactions provides critical insights for developing targeted therapeutic interventions. This review synthesizes current literature to elucidate the mechanistic basis of fever development and identifies potential therapeutic targets for clinical management.
Fever, defined as an elevation of core body temperature above normal circadian variation, represents one of the most conserved and ancient defence mechanisms in vertebrates. [Brown et al., 2019; Smith & Johnson, 2020] The pathophysiology of fever involves a sophisticated interplay of cellular and molecular events that coordinate the host's response to various pathogenic stimuli. Central to this process is the activation of immune effector cells, particularly mast cells, which serve as critical mediators in translating antigenic recognition into systemic inflammatory responses. [Williams et al., 2021; Anderson & Davis, 2018] Mast cells, originally described by Paul Ehrlich in 1878, are tissue-resident immune cells derived from hematopoietic progenitors that differentiate under the influence of local micro environmental factors. [Thompson et al., 2020; Lee & Martinez, 2019] These cells are strategically positioned at host-environment interfaces, including the skin, respiratory tract, and gastrointestinal system, where they function as sentinel cells capable of rapid response to antigenic challenges. The activation of mast cells through various triggers, including allergens, pathogens, and inflammatory mediators, results in the rapid release of preformed mediators and the synthesis of newly formed inflammatory compounds. [Garcia et al., 2021; Roberts & Wilson, 2018] Among the mediators released by activated mast cells, histamine occupies a central position due to its potent vasoactive and inflammatory properties. [Kumar et al., 2020; Zhang & Taylor, 2019] Histamine exerts its effects through four distinct G-protein coupled receptors (H1-H4), each with specific tissue distribution patterns and downstream signalling cascades. The interaction between histamine and its receptors initiates a complex series of events that influence vascular permeability, smooth muscle contraction, and immune cell recruitment, all of which contribute to the inflammatory milieu associated with fever development. Parallel to the histamine-mediated pathways, the cyclooxygenase enzyme system plays a pivotal role in fever pathogenesis through the synthesis of prostanoids, particularly prostaglandin E2 (PGE2). [Miller et al., 2021; Chen & Rodriguez, 2018] The COX enzymes, existing as two main isoforms (COX-1 and COX-2), catalyze the conversion of arachidonic acid to prostaglandin H2, which serves as a precursor for various bioactive prostanoids. The differential expression and regulation of these enzymes, particularly the inducible COX-2 isoform, represents a critical control point in the inflammatory response and fever development.
Ankita Singh, Aftab Ansari, Komal Singh, Rani Kumari, Sha Chandankumar Manojkumar, Navin Singh, Parinika Kumari, Mintu Prajapati, Shaesta Firdous, Nirjala Kumari, Priyanjali, Priya Kumari, Sudhir Kumar Yadav, Aman Kumar, Pushpa Kumari, Vishal Kumar, Suman Roy, Arnab Roy*, The Interplay Between Antigen-Induced Mast Cell Activation, Histamine Release and Cyclooxygenase Enzyme Activity in the Pathogenesis of Fever: A Comprehensive Review, Int. J. Sci. R. Tech., 2025, 2 (10), 01-12. https://doi.org/10.5281/zenodo.17239572
10.5281/zenodo.17239572
