THE FEBRILE RESPONSE TO INFECTIOUS MICROORGANISMS AND NEUROLOGICAL DISORDERS

S. Martinotti¹

¹Unit of Molecular Biology and Predictive Medicine, Department of Medical, Oral and Biotechnological Science, University of Chieti-Pescara, Chieti, Italy
*Correspondence to:
Stefano Martinotti, MD
Unit of Molecular Biology and Predictive Medicine,
Department of Medical, Oral, and Biotechnological Science,
University of Chieti-Pescara,
Chieti, Italy
e-mail: smartinotti@unich.it

Keywords: IL-1; febrile response; fever; infection; neurological disorders; brain

INTRODUCTION

Microbial infections can be located ubiquitously in all body tissues and are life-threatening. They cause acute-phase defensive responses that can affect homeostatic, metabolic, and immunological processes (1). Microorganisms such as bacteria are a common cause of infections that can affect all or parts of the body. The bacteria can affect the lungs, for example, in respiratory disease, but infections outside the lungs can also be present. The central nervous system (CNS) and one site may be involved with fever and systemic inflammation (2).  It is known that the hypothalamus in the brain mediates the febrile phenomenon and is involved in host defense by modulating the immune system (3). Therefore, host immunity against pathogenic infections causes neuroinflammatory responses and can give rise to feverish phenomena.

Interleukin-1 induces fever and affects the CNS

Interleukin-1 (IL-1) is a very important inflammatory cytokine that mediates the acute response after microbial invasion, with biological effects on all organs and tissues (4). It is mainly responsible for fever and is mostly synthesized by macrophage cells stimulated by microorganisms and parts of them (5). IL-1 affects RNA transcription and acute phase protein synthesis by inducing C-reactive protein, serum amyloid A (SAA), complement components, and other inflammatory mediators, with decreased albumin (6). IL-1 stimulates endothelial cells in the brain, promoting angiogenesis and microorganisms cause these cells to release IL-1 and mediate inflammation (7). IL-1 produced by endothelial cells causes various pathological effects including vasculitis. Furthermore, IL-1 activates the endothelial cells to produce adhesion molecules, prostaglandin PGE2, and prostacyclin PGI2, the latter both involved in vasodilation and favoring edema and leakage of blood cells from the vessels (8).

IL-1 also affects fibroblasts where it stimulates mitosis and the production of PGE2 and granulocyte-monocyte colony-stimulating factor (GM-CSF), mediating fibrosis (9). IL-1 induces fever in rodents that is similar to bacterial endotoxin, with increases in adrenocorticotropic Hormone (ACTH) and various acute phase proteins with decreases in neutrophil counts and many other biological effects (5). IL-1 also acts on the mesangial cells of the kidney and on the glial cells which, together with the neurons, make up the nervous system (10).

IL-1 induces fever by involving the hypothalamus, where the body’s temperature regulation center resides, and where pro-inflammatory cytokines, such as IL-1, are released (11). There are many cytokines that act at the hypothalamic level as an endogenous pyrogen, for example IL-1a, IL-b, tumor necrosis factor (TNF), Interferon-a, Interferon-b, Interferon-y and others, although the exact mechanism of action has not yet been clarified (12).

Microbes and their products, such as endotoxin, and IL-1 induce fever with activation of hypothalamic endothelial cells and PGE2 synthesis (8). The release of neurotransmitters activates the cerebral vasomotor center, generating vasoconstriction which retains heat with an increase in the febrile temperature (13). Microorganisms cause brain infection by activating glial and neuronal cells with the production of pro-inflammatory cytokines, including IL-1, IL-6, and TNF, that produce fever when injected intravenously or into the third ventricle in rats (14). At the therapeutic level, blocking IL-1 with IL-1 receptor antagonist (IL-1Ra) or IL-37 is known to reduce fever (15) and since IL-1 induces PGE2, non-steroidal anti-inflammatory drugs blocking cyclooxygenase-2 inhibit fever (16). Therefore, IL-1 is a major pro-inflammatory molecule and is related to TNF, which has different receptors than IL-1. It is expressed by almost all human cells and organs, in the brain, and physiologically participates in the regulation of cell growth and reparative processes. This cytokine mediates a large number of pathological effects, including inflammation of organs and tissues, and plays a crucial role in the pathogenesis of disease (17). In fact, blocking this cytokine improves the pathological state of disease (18).

CONCLUSION

In the last twenty years, new members of the cytokine family have been discovered and the IL-1 genes have been found to be located on chromosome-2 (19). In the CNS, IL-1 is produced by both immune cells and non-immunocompetent cells (20). The synthesis of IL-1 in the brain leads to a series of pathology with inflammation and neurological defects. IL-1 produced by microorganisms after an infection reaches the brain through disruption or impaired permeability of the blood brain barrier (BBB). IL-1 passes the BBB through the alteration of endothelial cells and can be generated or reach the CNS via the vagus nerve, other nerve fibers, or via microglia which produce it locally upon activation. In the acute phase of ischemic stroke with cerebral hemorrhage, there is strong IL-6-mediated inflammation that can be reduced with the IL-1Ra, since IL-1 induces IL-6. In fact, stroke severity correlates with high IL-1 levels.

These results demonstrate a close relation between IL-1 secreted during microorganism infection, the brain and brain disease, stroke, and fever.

Conflict of interest

The author declares that they have no conflict of interest.

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