IL-2, generated exclusively by activated Th1 and CD8+ T cells, plays a crucial role in T-cell proliferation and immune regulation. It activates JAK1/3 and STAT5 via a trimeric receptor complex (CD25/CD122/CD132). After being phosphorylated, STAT5 moves to the nucleus where it promotes the transcription of cell cycle genes (Cyclin D2) and the IL-2Rα (CD25) gene itself (a positive feedback loop). This signaling is very important because it is paired with the activated PI3K/Akt/mTORC1 pathway, which makes GLUT1 more active and speeds up glycolysis (the Warburg effect), thus providing the biomass necessary for the proliferation of effector T-cells (Figure 1A). Simultaneously, low-level IL-2 signaling is required for regulatory T cells (Tregs), increasing B-cell lymphoma 2 (Bcl-2) expression and ensuring their survival and suppressive activity (5). In adult CAP, circulating IL-2 levels are markedly increased relative to healthy controls (Median: 5.67 vs. 2.13 pg/mL; p < 0.001), signifying active infection and corroborating its use as a diagnostic adjunct (6).

However, its utility varies greatly with age. In adults, levels correlate with severity scores (CURB-65, PSI). Its overall performance is moderate but a value> 10.40 pg/mL offers the highest specificity (97%) for death of all markers and independently predicts mortality (HR 1.016), outperforming IL-6 in differentiating high-risk status (6). In the elderly (≥65 years), however, its prognostic significance weakens, probably reflecting immunosenescence and impaired T-cell responses (7). Pediatric observations suggest a more nuanced picture: whereas bronchoalveolar lavage fluid (BALF) levels are locally raised, systemic levels may be decreased in severe cases, suggesting a possible protective impact via Treg activation in early life (8, 9).

M1-polarized macrophages and endothelial cells are the principal sources of IL-6 during the acute phase. They respond to recognizing pathogens and control the acute-phase reaction as a whole. Biologically, IL-6 exerts pleiotropic effects via two distinct signaling paradigms. First, homeostatic cis-signaling occurs when IL-6 binds membrane-bound IL-6R on hepatocytes and immune cells. This activates the JAK/STAT3 pathway to induce C-reactive protein (CRP) synthesis and, crucially, promotes resolution by stimulating the release of anti-inflammatory mediators like IL-1Ra and IL-10. Second, under inflammatory stress, the pathological trans-signaling pathway dominates. Here, the soluble IL-6R/gp130 complex activates the SHP-2/Ras/MAPK signaling pathway in cells lacking membrane receptors (e.g., endothelial cells, Figure 1B). While this mechanism is necessary for leukocyte recruitment, its excessive activation blocks VE-cadherin and strengthens the NF-κB loop, which leads to the cytokine storm and vascular leakage (10, 11). This eventually results in systemic inflammatory response syndrome (SIRS), acute respiratory distress syndrome (ARDS), and multiple organ dysfunction syndrome (MODS) (12). Crucially, as a primary stimulator of tissue factor and plasminogen activator inhibitor 1 (PAI-1), elevated IL-6 links inflammation and coagulation, thereby predisposing severe CAP patients to immunothrombosis and pulmonary embolism (13).

Clinically, the extent of this inflammatory response correlates significantly with patient outcomes. Regarding its diagnostic value, serum IL-6 levels in healthy baselines are modest (~5 pg/mL), whereas systemic values above 100 pg/mL indicate deteriorating oxygenation and radiographic deterioration (14). Moreover, significantly elevated amounts differentiate bacteremic CAP (Mean: 2,852 pg/mL) from viral or other causes (≤300 pg/mL). In addition, IL-6 has higher prognostic performance over PSI for predicting 30-day mortality (AUC 0.934) and offers an early diagnosis window 24-48h before the development of symptoms (7, 15). Longitudinal surveillance is necessary; sustained titers in older patients independently predict death (OR 5.39) for the indication of antibiotic escalation (7). Moreover, the efficacy of IL-6 receptor antagonists (e.g., Tocilizumab, Sarilumab) in decreasing mortality among critically ill patients (the RECOVERY and REMAP-CAP trials) has substantiated the trans-signaling pathway as a viable therapeutic target, representing a paradigm change in the management of severe viral CAP (10).

Within 72 hours after symptom onset, alveolar macrophages and epithelial cells produce IL-8, which serves as a chemoattractant for neutrophils. It stimulates the PI3K/Akt pathway by binding to the G-protein-coupled receptors CXCR1 and CXCR2. This controls not only chemotaxis but also respiratory burst and degranulation (Figure 1C) (16). Mechanistically, IL-8 binding triggers a rapid intracellular calcium influx. In cases of severe infection, this calcium surge directly triggers the nuclear translocation of peptidylarginine deiminase 4 (PAD4). PAD4 citrullinates histones, which makes chromatin less dense and releases Neutrophil Extracellular Traps (NETs) in an enormous way. These released DNA-histone complexes have direct cytotoxic effects on the alveolar epithelium, which leads to consolidation and immunothrombosis (17, 18).

Given its direct contribution to tissue injury, IL-8 is an effective risk classification tool, especially in pediatric and severe adult CAP. In a pediatric cohort, IL-8 levels were significantly higher in severe cases compared to non-severe cases (Median: 120 vs. 50 pg/mL; p < 0.001) and showed superior predictive capability for in-hospital mortality compared to CRP and procalcitonin (PCT) (AUC 0.877 vs. 0.75 and 0.80, respectively), establishing itself as an independent prognostic factor (19). In adults, IL-8 levels are also linked to PSI scores and the probability of hospitalization. Inpatients have much higher levels than outpatients (Median: 34,763 vs. 14,696 pg/mL; p = 0.001), and they are much more likely to need mechanical ventilation (HR 1.42) (20). Unlike the temporary rise in IL-6, the increase in IL-8 often persists for 3–5 days or longer in unresponsive patients (16), which is associated with longer-lasting lung damage and the development of ARDS (21).

IL-12 is usually produced by activated dendritic cells (DCs) and macrophages in response to microbial stimulation. It functions as a key regulator of type 1 immunity, regulating innate and adaptive immune responses (Figure 1D). By interacting with the IL-12R/β1/β2 complex on NK cells and naive T cells, IL-12 stimulates the JAK2/TYK2/STAT4 signaling pathway. This activation is essential for promoting the differentiation of Th1 cells and resulting in substantial production of interferon-γ (IFN-γ), which is important for activating macrophages to eliminate intracellular pathogens (e.g., Legionella, viruses) (22).

In the context of CAP, the role of IL-12 is dependent on both the stage of the disease and its underlying cause. During the initial hyper-inflammatory phase of viral pneumonia, such as Influenza A, increased levels of IL-12, along with IL-6, exacerbate the cytokine storm and subsequent tissue damage. Conversely, a diminished IL-12 response is frequently observed in cases of severe bacterial sepsis. This phenomenon, termed “immunoparalysis”, is characterized by monocyte exhaustion and the downregulation of HLA-DR (Major Histocompatibility Complex, Class II, DR Alpha), which correlates with an impaired ability to resolve secondary infections (23). In addition, reduced levels of IL-12p70 in septic patients have been linked to heightened mortality, thereby serving as a biomarker for immune suppression that may be responsive to immune-stimulating treatments rather than anti-inflammatory interventions (20).

The IL-7/IL-7R axis is necessary for the survival and proper growth of both naïve and memory T cells. Instead of hematopoietic sources, IL-7 is primarily secreted by stromal and epithelial cells in the bone marrow and lymphoid tissues, essential for maintaining the T-cell pool. When CD127 (IL-7Rα) delivers a signal, it activates STAT5, which raises the levels of anti-apoptotic molecules (Bcl-2, Mcl-1) to prevent cell death. In severe CAP, this axis shows significant “axis suppression,” which is marked by low levels of IL-7 and high levels of soluble IL-7R (sIL-7R, a decoy receptor, Figure 1E). This dysregulation directly leads to the absolute lymphopenia that is often seen in sepsis, making it more challenging for the immune system to clear viruses and increasing the probability of developing secondary infections (24, 25).

Clinically, this depletion is apparent as severe CAP patients suffer from significantly reduced IL-7 levels (Median: 6.8 vs. 12.4 pg/mL) alongside elevated sIL-7R levels. sIL-7R (>25.04 ng/mL) functions as an independent predictor of 30-day mortality (HR 3.42) (24). Consistent with this, external IL-7 administration could ameliorate sepsis-induced lymphopenia and increase CD4+/CD8+ T-cell counts (26). Moreover, decreased IL-7R expression in BALF is associated with an increased pathogen burden, supporting its function in local immune competence (27).

IL-10, mostly derived from Tregs, Th2 cells, and M2 macrophages, functions as a powerful immunoregulator. It interacts with the IL-10R1/R2 complex and activates the JAK1/TYK2/STAT3 axis. Phosphorylated STAT3 activates SOCS3 to inhibit pro-inflammatory signaling. More importantly, it blocks the transcription factor CIITA. This epigenetic silencing reduces the expression of surface HLA-DR on monocytes, which makes it harder for them to deliver antigens (Figure 1F) (28). Nevertheless, its role within severe CAP is paradoxical: high levels often signify a robust compensatory response to intense inflammation. This intense immunosuppressive state sets the stage for subsequent bacterial superinfections such as post-influenza aspergillosis and S. aureus pneumonia, which are major drivers of late mortality (29).

The IL-6/IL-10 ratio is an important indicator for evaluating this subtle balance between pro-inflammatory drive and compensatory anti-inflammatory resolution. Mechanistically, these two cytokines are closely linked via a negative feedback loop: circulating IL-6 acts as a regulatory factor that directly induces the transcription of IL-10 in T cells and macrophages (discussed in Section 2.1.2). In a functional immune system, a surge in IL-6 triggers a proportional rise in IL-10 to limit tissue damage. Therefore, a pathologically high IL-6/IL-10 ratio signifies not merely excessive inflammation, but a disruption of this homeostatic coupling—indicating that the compensatory anti-inflammatory response is insufficient to counteract the cytokine storm. Clinically, this imbalance is a potent predictor of adverse outcomes. For example, a ratio of 9.61 or more in children correlates with severe disease (PPV 93%) (30), whereas IL-10 levels >14.7 pg/mL after 48 hours differentiated nonsurvivors in adults more specifically than any other variable (96% specificity) (31). Genetic predisposition, along with circulating levels, also affects severity. The IL-10-1082G/A polymorphism is inherently associated with disease progression, with the G allele and GG genotype being markedly prevalent in severe and fatal cases (32). Thus, long-term elevation of IL-10 indicates not simply “anti-inflammation” but also immunoparalysis, a lethal status to monitor for complications occurring in hospitals.

Activated macrophages and epithelial cells produce IL-37, a broadly effective suppressor of innate immune responses. Mechanistically, it operates by a dual mechanism (Figure 1G): extracellularly, it binds to IL-18Rα and recruits SIGIRR (IL-1R8) to produce a “dead” decoy complex that can suppress NF-κB signaling; intracellularly, caspase-1-cleaved IL-37 translocates to the nucleus in the presence of Smad3 to epigenetically mute pro-inflammatory genes (33). Clinically, the serum level of IL-37 is inversely correlated with illness severity, duration of hospitalization, and mortality in CAP (34). Combining IL-37 with PSI provides a better prediction accuracy (AUC 0.911) than using risk scores alone. However, its impact is markedly pathogen-dependent. In viral pneumonia (e.g., Influenza), IL-37 is protective, attenuating excessive lung injury (34, 35). Conversely, in bacterial models (S. pneumoniae), IL-37-mediated immunosuppression impairs neutrophil recruitment and bacterial clearance, paradoxically worsening survival (36). Thus, evaluating IL-37 levels requires a classification of the pathogen within this dual role.

IL-4 is the main cytokine for Th2 cells, basophils, and type-2 innate lymphoid cells (ILC2). It has two roles that are controlled by IL-4Rα/STAT6 signaling. Its role in CAP varies significantly depending on the situation (37). In the context of recovery, such as convalescent viral or pediatric CAP, IL-4 offers protection by promoting the polarization of alveolar macrophages towards the reparative M2 phenotype, thereby enhancing Arginase-1 (Arg1) to generate polyamines for collagen synthesis and epithelial regeneration (38) (Figure 1H).

During acute bacterial or intracellular infections (Mycoplasma, Chlamydia), IL-4 induces a maladaptive Th2 skewing. This suppression starts in T-cells, where IL-4-activated STAT6 triggers GATA3, which transcriptionally silences T-bet. This stops the generation of IFN-γ, which is needed to activate macrophages. The problem is exacerbated downstream within macrophages: activated STAT6 physically locks away the limited transcriptional co-activators CBP/p300, hindering the bactericidal STAT1 signaling pathway even though there are still cytokines around (39). Clinically, high levels of IL-4 are linked to lobar consolidation and severity in Mycoplasma pneumonia, which is a sign of harmful immunologic deviation (40).

IL-17, mainly produced by Th17 and γδ T cells, facilitates mucosal defense (Figure 1I). Rather than act directly on neutrophils, it interacts with the IL-17RA/RC complex on epithelial and endothelial cells, bringing in the adaptor Act1 to recruit TRAF6 as well as phosphorylate and inactivate the RNase Regnase-1. This post-transcriptional mechanism stabilizes the mRNA of chemokines (e.g., CXCL8, IL-6), which allows rapid and efficient neutrophil mobilization (41). This process is crucial for strengthening the epithelial barrier and eliminating extracellular bacteria (S. pneumoniae, A. baumannii); knockout mice models demonstrate markedly decreased survival owing to impaired clearance (42, 43).

However, when IL-17 levels exceed a particular threshold (>50 pg/mL), it causes a “hyper-inflammatory” state. In this setting, it actively lowers the amounts of tight junction proteins like Claudins and Occludin, which weakens the epithelial barrier and allows excessive neutrophils to enter (44). The increase is frequently stimulated by mucosal-associated invariant T (MAIT) cells, which show skewed activation in severe pediatric CAP (45).

Traditionally regarded as a hematopoietic growth factor, IL-3 has recently been found as a significant regulator in sepsis. This cytokine is mostly released by a specific kind of B cells, called Innate Response Activator (IRA) B cells, during sepsis caused by pneumonia. When recognizing infectious substances, these cells migrate to the spleen and lungs. There, they release IL-3, which then travels via the bloodstream to the bone marrow. This signaling promotes “emergency myelopoiesis”, driving the fast proliferation and mobilization of Ly-6C monocytes and neutrophils, thereby exacerbating the systemic inflammatory response (Figure 1J) (46).

Clinically, IL-3 acts as a “double-edged sword” biomarker, with its effects dependent on the particular cause. In bacterial sepsis, high levels of IL-3 in the blood (>127.5 pg/mL) are linked to increased inflammation and independently predict death. In contrast, in severe viral pneumonia (e.g., SARS-CoV-2), IL-3 protects the lungs by recruiting plasmacytoid DCs for local antiviral defense. Consequently, low IL-3 levels in viral sepsis are associated with viral reactivation and poor prognosis (47, 48). Thus, IL-3 serves as a context-dependent biomarker: marked elevation warns of bacterial-induced hyper-inflammation, whereas depletion signals viral-associated immune failure.

As a member of the IL-12 family, IL-27 is mainly released by macrophages and DCs. It is an important immunoregulator that connects innate and adaptive immunity. The cytokine uses a “dual-signaling” signaling pathway through WSX-1/gp130 (Figure 1K). This stimulates STAT1 to promote Th1 differentiation (through T-bet induction) and enhance bacterial clearance. It also activates STAT3 to make Tr1 cells that make IL-10 and inhibit Th17 cell proliferation (49).

Its kinetic profile offers an additional benefit for clinical use. Unlike the transient spike observed in IL-6, IL-27 shows a more sustained rise that can persist for 72–96 hours and longer during bacterial infections (50), which gives a wider diagnostic window (51). Studies on pediatric and adult CAP demonstrate that IL-27 outperforms PCT in differentiating between bacterial and viral etiologies (AUC>0.85) (52). Besides diagnosis, admission levels are tightly linked to the level of bacteria burden and the severity of sepsis. IL-27 is an independent predictor of prolonged hospital stays and death in critically ill patients (51). These characteristics make IL-27 an appealing option for guiding antibiotic stewardship decisions.

IL-33 is usually kept in the nuclei of pulmonary epithelial cells, which is different from circulating cytokines that leukocytes release. It acts as an “alarmin” by being passively released upon cellular necrosis, delivering signals to ILC2s and Th2 cells through the ST2 (IL-1RL1) receptor and MyD88 pathway (Figure 1L). This distinct release mechanism makes IL-33 a direct biomarker for epithelial barrier integrity and lung tissue damage (46). When the system is stable or has only mild injury (like seasonal flu), IL-33 helps repair tissue. It accomplishes this by prompting ILC2s to secrete Amphiregulin (Areg), an epidermal growth factor essential for epithelial regeneration (47).

In cases of severe viral CAP (e.g., SARS-CoV-2), the situation alters. In this instance, persistent and excessive IL-33 release disrupts the reparative pathway, leading to maladaptive type-2 inflammation, airway hyper-responsiveness, and pulmonary fibrosis. Clinically, serum IL-33 levels correlate with the radiographic severity of viral pneumonia and assist in predicting development to ARDS (48). sST2 (the soluble decoy receptor) is generally a better predictor of outcomes than IL-33 itself. High sST2 levels are a strong independent predictor of 30-day mortality and complications from heart failure in hospitalized CAP patients (49).