Inflammatory bowel disease (IBD) is a multifactorial disease of the digestive tract. Their prevalence has increased considerably over the previous decade due to industrialization and changes in people’s lifestyles. These are incurable diseases whose management is not unanimous because patients react differently to the treatment administered. Therefore, the search for new therapeutic targets is continuous to find better treatment, to reduce the periods of crisis, and to improve the health of the patients. In view of this fact, we have in this article brought together the various therapeutic targets associated with these pathologies to produce effective care against inflammatory bowel diseases.

Inflammatory bowel disease, Crohn’s disease, Ulcerative colitis, Cytokines, Shingosine-1-phosphate, Exosomes, Transcription factors.

Inflammatory bowel diseases are chronic and recurrent conditions affecting the digestive tract.[1] They are represented by various conditions such as ulcerative colitis, crohn’s disease, and undetermined colitis. Crohn’s disease differs from other IBD in that it is located in the entire gastrointestinal tract, with an initial location in the ileum and cecum, whereas ulcerative colitis is mainly found in the colon.[2] The main manifestations of these conditions are non-bloody diarrhea, abdominal pain, and the appearance of a yellowish fatty mass in the lower right quadrant of the abdomen.[3] Fever and myasthenia with complications such as fistulas to the bladder, hepatitis abscesses, lymphatic aggregation and growth retardation in children. The expansion of these diseases across the globe is a result of industrial advances and the lifestyle of populations. Indeed, the highest incidence of Ulcerative colitis (UC) has been currently recorded in Europe (24.3/100,000), while the new cases of Crohn’s disease (CD) have been mainly recognized in North America (20.2/100,000).[4] Although all ages are predisposed to the disease, there is a high incidence between 17-39 years for Crohn’s disease and 40-64 years for ulcerative colitis. Females are 2.83% more likely to be affected by these diseases than males. However, the spread of these diseases around the world is increasing. Indeed, numerous cases in Asia, Latin America, and Africa show the need to take repressive measures to stop their spread.[5]

Although their etiology is poorly understood, a multifactorial cause has been stated namely genetic predisposition involving the expression of 242 genes including autophagy related 16 like 1 (ATG16L1), cadherin 1 (commonly known as E-cadherin; CDH1), hepatocyte nuclear factor 4 alpha (HNF4a), interleukin 10 (IL10), interleukin 10 receptor alpha (IL10RA), interleukin 10 receptor beta (IL10RB), interleukin 23 receptor (IL23R), immunity-related GTPase M (IRGM), leucine-rich repeat kinase 2 (LRRK2), nucleotide-binding oligomerization domain containing 2 (also known as CARD15; NOD2), and protein tyrosine phosphatase non-receptor type 2 (PTPN2), which are involved in innate mucosal defense, Paneth cells, epithelial barrier, immune cell recruitment, antigen presentation, T cell regulation, immune tolerance, endoplasmic reticulum stress, cellular oxidative stress and cellular apoptosis.[6-12] Environmental factors such as tobacco, food, drugs, and immune dysfunction. Irritation of the intestinal wall by food, certain xenobiotics, or bacteria from the microbiota results in elevated expression of toll-like receptors (TLRS 4 and 5) by the cells of the intestinal wall (enterocytes, paneth cells, etc.), which promotes abnormal recognition of antigenic markers.[12] There is a continuous recruitment of macrophages, neutrophils, and dendritic cells that produce pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-12, and IL-2 following the activation of nuclear factor (NF-kB). There is also the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) by macrophages and excessive production of lysosomal myeloperoxidase (MPO) by neutrophils and macrophages, which destabilize cell membranes. This process is maintained by TH1 and TH17, which produce IFN-γ, IL-17, TNF-α, and IL-12, promoting differentiation into the M1 phenotype of macrophages at the expense of the M2 phenotype.[13-15] There is also an inhibition of regulatory T cells (Tregs).[1] Similarly, inhibition of the production of hemoxygenase 1 (HOX-1) by inhibition of the NRF-2 factor results in a decrease in carbon monoxide (CO), which, in normal conditions, prevents the function of antigen presentation by dendritic cells and macrophages and allows the activation of Tregs.[16-17]

IBD is a disease that is currently incurable and for which the search for new therapeutic targets is ongoing. Medical research aims to increase the periods of remission and decrease the periods of crisis, even though with age, the periods of remission become shorter and shorter. As a result, several therapeutic targets in the signaling pathways of IBD have been identified for effective treatment, although the search for new therapeutic targets is ongoing.

For this review study on therapeutic targets associated with the treatment of IBD, the databases PubMed and Embase were systematically studied. Publications on studies of IBD, mainly on CD and UC, were selected. Subsequent screening was performed. This allowed only articles on the study of specific markers of IBD to be retained. Therefore, a list of therapeutic targets was established during drug research associated with IBD. Articles that did not address IBD were excluded, as well as those that were not in English or French.

Various published articles were reviewed, and six groups of therapeutic targets were referenced.

Integrins: These are heterometric transmembrane receptors of leukocytes formed by 2 subunits, α and β. The α4β7 integrin are found on gut-related lymphocytes, α4β1 are present on the surface of leukocytes and αEβ7 (Table 1) are expressed by intraepithelial T cells, dendritic cells and regulatory T cells, On vascular endothelial cell adhesion molecule-1 (VCAM-1), mucosal addressing cell adhesion molecule-1 (MadCAM-1) of endothelial cells and E-cadherin on mucosal epithelial cells.[18-19] During intestinal inflammation, there is an increase in the expression of cell adhesion molecules that induce the recruitment of leukocytes and lymphocytes to the intestinal mucosa, which are essential for the maintenance of inflammation.[20]

Table 1: Some therapeutic targets and their antagonists

Cytokines
TNF-α: It is an essential cytokine for the maintenance of the inflammatory response. It is involved in various biological activities such as apoptosis, cell proliferation, inflammation, and many others.[1,21] Overexpression of this cytokine is the cause of several chronic diseases such as IBD, rheumatoid arthritis, and psoriasis. Poor regulation of the metabolism of this cytokine leads to the maintenance of a permanent inflammatory state (Table 1). It binds two specific receptors: TNFR1, which is expressed by all human cells and is therefore a key point in TNF-α signaling, and TNFR2, which is present on immune cells.[22,23]  TNFR1 signaling is involved in cytotoxic and proinflammatory responses, while TNFR2 signaling is involved in cell proliferation, activation, and migration. It is the main therapeutic target involved in drug discovery for IBD.[24-26]

IL-12 AND IL-23: These are pro-inflammatory cytokines involved in the pathogenesis of IBD. IL-12 consists of 2 subunits p35 and p40 while IL-23 consists of p19 and p40 (Table 1). IL-12 is involved in the activation of CD4+ lymphocytes and the differentiation of T cells into TH1, which are producers of interferon (IFN) γ, which is a proinflammatory cytokine. IL-23 is involved in the formation of TH-17, which also produces IFN-γ and IL-17.[27-30]

Enzymes
Janus Kinase: It is a family of 4 tyrosine kinases (JAK1, JAK2, JAK3, and tyrosine kinase 2) that interact with a family of 7 proteins: The Signal Transducers and Activators of Transcription (STATs).[31] JAK3 is expressed specifically by TH-17, while the other 3 are ubiquitous.[32] JAK2 is involved in IL-23 production, while TYK2 is involved in IL-12 production. Those two interleukins are the most implicated in Crohn’s disease physiopathology. The JAK-STAT signaling pathway is involved in the production of 60 cytokines, hormones, and growth factors in Crohn’s disease and IL-5, IL-9, IL-13, and IL-33 for ulcerative colitis (Table 2).  This signaling pathway plays an important role in innate and adaptive immunity, hematopoiesis, cell growth, and cell differentiation (Figure 1).[33-36]

Figure 1: JAK/STAT pathway signaling scheme

Table 2: Implications of some enzymes in inflammatory bowel disease and their inhibitors

Myeloperoxidase: It is a dimer present in high concentration (2 to 5% by weight) in the primary granules of neutrophils and in small quantities in monocytes, which lose it during their differentiation into macrophages.[37-39] It is involved in many pathologies such as arthritis, lung infections, and IBD. The neutrophils responsible for their production have a strong affinity with the intestinal endothelium. This enzyme is released into the intestinal lumen during inflammation during neutrophil degranulation.[40] It catalyzes the hydrolysis reaction of H2O2 to HClO, which oxidizes the intestinal cell membranes (Figure 2). During inflammatory bowel diseases, there is an increase in the production of this enzyme, which is correlated with the level of neutrophils present in the intestinal lumen (Table 2). It plays an important role in cellular messenger immunity via the activation of transcription factors (NF-κB) and in the induction of apoptosis via the caspase pathway. Its production by macrophages remains limited. Similarly, the HClO produced activates the nuclear translocation of the NF-κB factor, which initiates the transcription and synthesis of many pro-inflammatory mediators.[41-45]

Figure 2: Mechanism of action of myeloperoxidase with production of reactive oxygen and nitrogen species

NADPH oxidase: It is an enzyme made up of 2 membrane subunits (Gp91phox and p22phox) and 4 cytosolic subunits (p40phox, p47phox, p67phox, and Rac).[46] It is present in neutrophils, and its production is correlated with the level of neutrophils present in the intestinal lumen (Table 2). The activation of this enzyme is via different signaling pathways through tyrosine kinase receptors, growth factor receptors or G protein-coupled receptors. The 2 main activation pathways of this enzyme are activation by phosphorylation of membrane receptors, protein kinase C (PKC), and activation by arachidonic acid and other fatty acids. It catalyzes the formation of the superoxide anion, which is a powerful oxidizing agent, thus causing the oxidative stress observed in these pathologies. It is the main enzyme of the respiratory outbreak (Figure 3).[47-50]

Figure 3: Mechanism of superoxide anion production by NADPH oxidase

Hemoxygenase-1: It is an enzyme that is a reference anti-inflammatory and antioxidant, and is expressed by various tissues in the body. HO-1 consists of 288 amino acid residues with its active site located between the first two alpha helices.[51] It converts heme to biliverdin, carbon monoxide (CO), and iron2+.[52] The CO produced inhibits the mitochondrial respiratory chain, thus preventing the phagocytic activity of macrophages. Similarly, the CO produced activates Tregs, which help to regulate the inflammatory response. The biliverdin produced decreases the expression of genes associated with cyclooxygenase-2, Nitric oxide synthase, prevents the infiltration of neutrophils into the wall of the jejunum, and decreases the production of IL-1β and IL-6 (Table 2).  Its activation is under the control of several mediators such as heme, hemin, cobalt-protoporphyrin, and nrf-2 (Figure 4).[53-56]

Figure 4: Hemoxygenase 1 activation mechanism by nrf2 and mechanism of action

Phosphodiesterase (PDE): PDE consists of a family of 7 isoenzymes that degrade cAMP and cGMP, which are implicated in the regulation of inflammation. Abnormal activation of PDE results in an abnormal response that leads to chronic inflammation of the intestinal wall. The main isoenzyme implicated in IBD is PDE4. PDE4 is a significant type of PDE family in immunocytes, which is responsible for degrading cyclic adenosine monophosphate (cAMP) in the cytoplasm. Some research reveals that high levels of cAMP in the cytoplasm can downregulate TNF-α generation in macrophages.[57-59] The use of PDE4 inhibitors increases cAMP and decreases the level of TNF-α as reported in research on the rat colon (Table 2). However, the main drugs that are actually used as PDE4 inhibitors show some inevitable adverse effects such as diarrhea, weight loss, nausea, and psychiatric events, which restrain the usage in UC management.[60-62]

Cyclooxygenase 2(COX-2): Cyclooxygenase consists of two isoforms, COX-1 and COX-2 that convert arachidonic acid to prostaglandins, protacyclins and thromboxans. These compounds play an important role in inflammation, such as vasodilatation to allow cell infiltration in inflamed tissues. COX-1 is produced under normal conditions, particularly in the endothelium, platelets, and kidneys, while COX-2 is inducible by inflammatory factors such as smoking, which is a risk factor in the etiology of Crohn’s disease (Table 2). COX-2 inhibitors are very interesting in IBD; however, they also block the production of PGI2, which is an important anti-aggregating agent.[63-68]

5-lipoxygenase(5-LOX): 5-LOX is an enzyme of a family of lipoxygenases that metabolize arachidonic acid into leukotrienes and lipoxins.[69] Certain Leukotriens like LTB4 play an important role in granulocytes and monocytes chemotaxis, recruitment, their degranulation with superoxide generation, increase cytokine production in LT cells, and increase permeability hyperalgesia, while LTC4 plays a role in intestinal contraction. All these mechanisms contribute in the development and maintain of IBD. Otherwise, lipoxins can be considered to have an antagonist role to leukotriens. They possess anti-inflammatory effects like LXA4 and LXB4, which reduce the production and chemotaxis of granulocytes and stimulate monocyte activation (Table 2). Lipoxins and synthetic lipoxin analogs inhibit transcription factors related to inflammatory processes like NF-κB, stimulate efferocytosis, reduce macrophage infiltration, and inhibit progression in some diseases such as atherosclerosis. All these make 5-lipoxygenase an interesting molecule in the regulation of IBD.[70-74]

Exosomes: They are small vesicles in biological fluids (urine, blood, milk, saliva, cerebrospinal fluid) formed from invaginations of lysosomes and which fuse with the cytoplasmic membrane before being released.[75] They are vesicles associated with intercellular communication through the transport of lipids, nucleic acids, and proteins (Figure 5).

Figure 5: Exosome presentation

They express on their surface cellular markets such as α4β7 which is an integrin that is sympathetic to Vedolizumab which is an antibody directed against this same integrin on CD4+, thus decreasing the effectiveness of the treatment. Similarly, a study conducted on mitochondrial RNA of serum exosomes shows their implications on pro-inflammatory cytokine production and macrophage recruitment (Table 3).[76-78]

Table 3: Different types of exosomes and their functions

Transcription factors
Signal transducer and activator of transcription (STAT3): STAT3 is a member of the seven STAT transcription factors, which are present in an inactive state in the cytoplasm of the cells.[79,80] The binding of the specific cytokine to the cell surface receptor results in the activation of a receptor-associated Janus kinase (JAK) and leads to the phosphorylation of STAT3, initiating the pathway.[81-83] Each STAT3 has an SH2 domain (A phosphotyrosine recognition domain) through which it reciprocally interacts with the other tyrosine-phosphorylated STAT3 monomer, followed by translocation into the nucleus to transcribe the target genes.[84-86] STAT3 has been identified as an oncogenic transcription factor that has a major role in malignant transformation.[87,88] Constitutive activation of STAT3 signaling has been observed in several types of human cancers and cell lines.[89,90] The JAK-STAT pathway regulates the expression of multiple mediators involved in inflammatory pathways implicated in the pathogenesis of IBD.[91-94]

Nuclear factor kappa B (NF-kB): NF-κB is a complex of NF-κB and IκB-α in the cytoplasm. Inflammatory cytokines and intestinal microorganisms activate the NF-κB transcription factor process by inducing the phosphorylation and consequent degradation of IκB by its kinase.[95-99] This allows NF-κB translocation into the cell nucleus to activate gene expression for relevant inflammatory proteins which lead to the production of pro-inflammatory cytokines such as TNF-α, IL-12, IL-23, enzymes like COX-2, NADPH oxydase and iNOS, which are secreted from the cell and propagate the immune response by acting on neighboring immune cells. Additionally, activation of NF-κB is implicated in the oxidative stress process.[100-105]

Nuclear factor erythroid 2-related factor 2 (NRF-2): Nrf2 (nuclear factor erythroid 2-related factor 2) is a stress-responsive transcription factor, associated with cellular homeostasis, which is regulated by the bound of Keap1in cytosol. However, upon stimulation by electrophilic agents or compounds that possess the ability to modify thiol groups, the Keap1-mediated repression of Nrf2 activity is lost, allowing the translocation of Nrf2 to the nucleus and the potentiation of the ARE response to regulate the activities of target genes such as SOD, CAT, and those of phase II detoxifying enzymes to remove harmful molecules such as reactive oxygen species (ROS). The critical role of Keap1/NRF2 signaling is implicated in both acute and chronic inflammation of diseases beyond IBD, including rheumatoid arthritis, gastritis, asthma, and atherosclerosis (Figure 4).[106-110]

Sphingosine-1-phosphate (S1P): S1P is a lipid associated with immune cell dynamics and inflammation. S1P signaling on central memory T-cells allows their exit from lymph nodes. Internalization of the S1P receptor prevents lymphocytes from responding to S1P, so they can’t reach the inflamed tissue (Table 1). The level of S1P increases with the disruption of the mucosa in inflamed Tissue, which leads to the recruitment of immune cells and persistent inflammation and tissue damage. Drugs targeting S1P can modulate the progress of lymphocytes from the lymph nodes, reducing their availability to contribute to inflammation in the gut and help maintain the integrity of the intestinal barrier.[111-113]

IBD is a chronic disease of poorly understood etiology that remains a challenge for modern research. These currently incurable diseases are the focus of various fundamental and medical studies aimed at improving the health status of patients. The continuous search for new treatments is based on therapeutic targets defined as a priority in the evolution of these diseases. Neutrophils, macrophages, and lymphocytes are the main cellular targets maintaining this inflammatory state through the expression of various surface integrins, the production of lytic enzymes, and pro-inflammatory cytokines. Although research is more oriented towards anti-TNF-α, researchers are looking for new and more general therapeutic targets that may have multiple actions on the repression of these pathologies and thus improve the periods of remission of IBD.

Not reported

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Corresponding Author:
Pechangou Nsangou Sylvain
Department of Biochemistry
University of Yaounde, Cameroon
Email: spechangou@gmail.com

Co-Authors:
Ngohoba Vigny Sayal, Njayou Frédéric Nico, Moundipa Fewou Paul
Department of Biochemistry
University of Yaounde, Cameroon

All authors contributed to the conceptualization, investigation, and data curation by acquiring and critically reviewing the selected articles. They were collectively involved in the writing – original draft preparation, and writing – review & editing to refine the manuscript. Additionally, all authors participated in the supervision of the work, ensuring accuracy and completeness. The final manuscript was approved by all named authors for submission to the journal.

This is a review study that does not involve human or animal subjects. Hence not applicable.

The author declares no conflict of interest.

None

https://doi.org/10.63096/medtigo3061214

Ngohoba VS, Pechangou NS, Njayou FN, Moundipa FP. Therapeutic Targets Associated with Medical Research in the Treatment of Inflammatory Bowel Disease. medtigo J Pharmacol. 2025;1(1):e3061214. doi:10.63096/medtigo3061214 Crossref