IL-6 AND IL-11 IN INFECTION

Grilli A, Prosperi GD. IL-6 and IL-11 in infection. International Journal of Infection. 2025;9(1):25-28.

A. Grilli^1* and G.D. Prosperi²

¹ Department of Medicine and Ageing Sciences, University “G. D’Annunzio” of Chieti- Pescara, Chieti, Italy.
² Department of Operative Dentistry, Dental School, University of Chieti, Italy.

*Correspondence to:
Alfredo Grilli,
Department of Medicine and Ageing Sciences,
University “G. D’Annunzio” of Chieti- Pescara,
Chieti, Italy.
e-mail: alfredo.grilli@unich.it

Received: 25 February, 2025 Accepted: 28 March, 2025

ISSN 1972-6945 [online] Copyright 2025 © by Biolife-publisher This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: all authors report no conflicts of interest relevant to this article.

ABSTRACT

Cytokines are secreted by the immune system and regulate immune and inflammatory responses. Interleukin (IL)-6 and IL-11 both belong to the IL-6 cytokine family and play crucial, but distinct, roles in infections and the immune response. IL-6 is a pro-inflammatory cytokine produced in response to pathogenic microorganisms by cells such as macrophages, dendritic cells, T lymphocytes, and endothelial cells. IL-6 plays a key role in the acute-phase response, helping the body react to infections and tissue damage and stimulates the liver to produce acute-phase proteins such as C-reactive protein (CRP), fibrinogen, and serum amyloid A. IL-6 also promotes B-cell maturation and antibody production, and supports T-cell differentiation and Th17 responses, which are important in bacterial and fungal infections. IL-11 regulates inflammation and has both pro- and anti-inflammatory potential. It can reduce the production of pro-inflammatory cytokines such as tumor necrosis factor (TNF) and IL-1β, and promotes cell survival and tissue regeneration and repair, as well as stimulating hematopoiesis. Both IL-6 and IL-11 are important regulatory cytokines of the immune and inflammatory response.

KEYWORDS: IL-6, IL-11, cytokine, infection, inflammation

INTRODUCTION

Cytokines are proteins secreted by immune system cells that regulate immune and inflammatory responses. During an infection, a cascade of cytokines is activated, stimulating the immune response to fight the infectious agent. Cytokines activate the vascular endothelium, promoting fever and the production of other cytokines, and anti-inflammatory cytokines limit the immune response to prevent tissue damage.

Interleukins (ILs) belong to the cytokine family and are important chemical messengers for the immune system, but when they increase excessively, they induce inflammation (1). Today, we know that there are also anti-inflammatory cytokines that could potentially be used to treat inflammatory diseases. Cytokines are capable of performing various functions and signaling, performing endocrine, autocrine and paracrine effects.

In the state of sepsis, many harmful molecules are produced, including inflammatory cytokines, which are important for the course of the disease (2). The first cells to intervene are macrophages which engulf the microorganisms. One of the soluble products released by Gram-negative bacteria is lipopolysaccharide (LPS), which activates macrophages to produce cytokines in vivo and in vitro. These cytokines are not only specifically activated by septicaemia, but can also be released after trauma, transplant rejection, ischemia, inflammation, hepatitis, myocarditis, and other diseases (3).

IL-6 and IL-11 both belong to the IL-6 cytokine family and play crucial roles in infections and the immune response. IL-6 is a pro-inflammatory cytokine produced by various cells such as macrophages, dendritic cells, T lymphocytes, and endothelial cells in response to pathogenic microorganisms such as bacteria and viruses. IL-6 plays a key role in the acute-phase immune response, helping the body react to infections and tissue damage. It stimulates the liver to produce acute-phase proteins such as C-reactive protein (CRP), fibrinogen, and serum amyloid A, which are biomarkers for inflammation. Furthermore, IL-6 promotes B-cell maturation and antibody production, and supports T-cell differentiation, particularly Th17 responses which are important in bacterial and fungal infections. IL-11 plays an important role in several physiological and pathological processes, including the immune response to infections. It regulates inflammation with an anti-inflammatory effect, reducing the production of pro-inflammatory cytokines such as tumor necrosis factor (TNF) and IL-1β. However, IL-11 may also have pro-inflammatory effects, such as those seen in the ageing process. IL-11 promotes cell survival, tissue regeneration and repair, and also stimulates hematopoiesis.

DISCUSSION

IL-6 participates in infectious processes by playing a role in host defence against microorganisms and is produced by many cell types, including macrophages. IL-6 does not induce the pro-inflammatory prostaglandin prostaglandin E2, but in hepatocytes in vitro, it can release serum amyloid A, an acute phase synthesis protein (4). In humans, low administrations of IL-6 (30 _/ug/kg) do not cause hypotension, while 100 ng/kg does. It has been found that high levels of IL-6, but not TNF, can be fatal in septicaemia. However, in certain pathologies, IL-6 can be a non-inflammatory, protective cytokine (5).

The biological functioning of IL-6 occurs through its binding to the gp130 receptor.  Therefore, cytokines of the IL-6 family (which has four a-helix bundle structure), use the common signaling glycoprotein of the 130 kDa receptor subunit (gp130), expressed by all cells of the body. Members of the gp130 cytokine family induce the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway, such as STAT3 and to a lesser extent, STAT1 (5). In some infectious diseases, IL-6 and IL-11 activate gp130, causing biological effects (6). The biological effects of IL-6 include the proliferation and differentiation of T lymphocytes, the induction of acute phase proteins, and the induction of immunoglobulin production in B cells.

For now, eight cytokines involved in the pathophysiology of B cells belong to the gp130 cytokine family (7). Blocking the activity of IL-6 with a monoclonal antibody (an effect similar to blocking TNF) is a strategy that is used in the therapy of some autoimmune diseases. Members of the IL-6 family share 4 helices with structural homology extending to cytokine receptors. Therefore, all cytokines of this IL-6 family that use the gp130 receptor have similar biological characteristics, but with different activities. IL-6 cannot be activated in the absence of its gp130 receptor (8).

The levels of IL-6 in the peripheral blood are approximately 3-6 pg/ml which increases up to many thousands in inflammatory states and in severe cases of septicaemia (9). In humans, the IL-6 gene is located on chromosome 7 and the protein has a molecular weight of 20-30 kDa and shows a certain homology with granulocyte colony-stimulating factor. The IL-6 receptor has a short intracytoplasmic region and, when activated by IL-6, does not induce signal transduction (10). The soluble IL-6 receptor, which increases under inflammatory conditions induced by infection, binds to the cytokine IL-6 and stimulates the membrane receptor gp130.

IL-6 deficiency in mice can induce a high susceptibility to bacterial infections, dysregulated haematopoiesis and may contribute to liver dysfunction, even if the mice appear phenotypically normal (11). Mice with alteration of the gp130 receptor are more sensitive to LPS and can develop gastric tumors and pulmonary emphysema (12). These results demonstrate a protective activity of this cytokine and show the importance of IL-6 in infections and other pathologies.

The cytokine IL-11 is part of the IL-6 family and is a monomeric protein that has pleiotropic effects (14). This cytokine induces signaling through an IL-11 α receptor complex and the gp130 β subunit (15). In several infections, IL-11 has been seen to be immunomodulatory by regulating pro-inflammatory cytokines. However, overexpression of IL-11 induces inflammation (mainly mediated by lymphocytes) and fibrotic remodelling (16).

IL-11 belongs to the IL-6 family and can activate pro-inflammatory signals such as JAK-STAT3, ERK-mTORC1, and NF-kB. IL-11 is upregulated in older people and is a marker of ageing (17). IL-11 stimulates platelet precursor megakaryocytes, promoting the production of platelets and is a multifunctional cytokine with significant roles in immune response modulation and haematopoiesis (18).  IL-11 uses the gp130 receptor (even in the absence of the IL-6 receptor) and has inflammatory effects; when produced in excess, it increases the levels of inflammation in several disease.

IL-11 has been shown to be effective in mucosal protection and repair of the mucosal lining of the gastrointestinal tract and modulates the immune response, preventing tissue damage during infections (19). Some research suggests that IL-11 levels may correlate with the severity of certain infections, indicating its potential as a biomarker. However, the role of IL-11 in viral infections is less clear.

It has been observed that some metalloproteinases cleave the IL-11 receptor bound to the cell membrane, generating the soluble IL-11 receptor capable of activating the gp130 receptor with biological effects (20).  Although it can help modulate the immune response, its overall effect can vary depending on the type of microorganism and the context of the infection. Its inflammatory properties make it a molecule of interest in the context of infections, where on the one hand, it could help control excessive inflammatory responses by protecting tissues, and on the other, it could increase inflammatory levels.

Proteins damaged during ageing are recognized by the immune system as if they were microorganisms and therefore non-self, and the immune system attacks them, causing inflammation. The triggered inflammatory process aggravates the pathological state and contributes to the formation of new diseases, including cancer. It has been seen that IL-11 is more abundant in older mouse tissues, including fat, skeletal, muscle, and liver tissue (13).

CONCLUSIONS

The cytokines IL-6 and IL-11 mediate hematopoiesis, immunity, and inflammation, and both share a signaling pathway via the gp130 receptor subunit. IL-6 is produced by macrophages, dendritic cells, fibroblasts, T lymphocytes, and B lymphocytes in response to viruses and bacteria and plays an important role in inflammation. IL-11 is generated primarily by fibroblasts, epithelial cells, and stromal cells, and can have both anti-inflammatory pro-inflammatory effects, along with providing tissue-protection and promoting the survival and regeneration of epithelial cells in the intestine and lungs.

Complications from streptococcal infections can induce the synthesis of pro-inflammatory cytokines and cause a high mortality rate (21). IL-6 has a pathophysiological action and is protective in macrophages treated in vitro with endotoxins. Using IL-11, another cytokine that utilizes the same subunit of the signal transduction receptor as IL-6, it was noted that the latter also has its own protective potential (22). Treatment of laboratory animals with an anti-IL-6 antibody increases mortality, demonstrating the ability of this cytokine to have a protective action against death. In these experiments, IL-11 was also protective against toxic shock syndrome (23).

IL-11 is mainly used in the therapy of chemotherapy-induced thrombocytopenia, in which low platelet counts occur, but its role in infectious diseases is still under research. IL-11 is a protein implicated in the ageing process. As recently reported in the medical literature, blocking IL-11 and its molecular partners appears to have a positive impact on longevity, but these studies still need to be confirmed (13). Therefore, in many international research laboratories, drugs that block this cytokine are being studied and are being tested against various diseases such as cancer, fibrosis, and chronic infections. According to a recently published article, IL-11 appears to counteract tissue ageing and impact lifespan (24). However, these results were observed in mice and may be different in human clinical trials. Ongoing research is exploring the potential therapeutic applications of IL-11 in infectious and inflammatory diseases.

Conflict of interest

The authors declare that they have no conflict of interest.

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