IL 11 Human

How does IL-11 signaling work in human cells?

IL-11 signaling occurs via a complex mechanism requiring specific receptor components. To signal in cis, IL-11 first binds to its cognate alpha receptor (IL-11RA in humans) and then binds to the shared gp130 (IL6ST) coreceptor. This interaction leads to dimerization with another IL-11:IL-11RA:gp130 molecule to form a hexameric signaling complex . This formation initiates canonical gp130-mediated signaling primarily through the JAK/STAT pathway, particularly JAK2/STAT3. Additionally, IL-11 activates multiple downstream pathways including ERK/P90RSK, LKB1/mTOR, and GSK3β/SNAI1 in both autocrine and paracrine signaling modes . These pathways collectively drive the pro-fibrotic, pro-inflammatory, and anti-regenerative effects observed in various tissues.

What is the structural organization of the human IL-11 receptor?

Human IL-11 receptor exists in at least two isoforms. The IL-11Rα1 isoform has a short cytoplasmic domain, similar to human IL-6 receptor and murine IL-11 receptors. The alternative isoform, IL-11Rα2, lacks this cytoplasmic domain, resembling the human CNTF receptor . The genomic structure of human IL-11Rα1 consists of 12 exons and 12 introns within a 9-kb genomic region, with the gene located on chromosome 9 at band 9p13 (notably, the CNTFR gene is also located at this position) . While murine and human IL-11 receptors share significant homology, the murine IL-11Rα gene contains 14 exons and shows evidence of developmentally regulated alternative first exon usage, adding complexity to comparative studies between species .

What methods are available for measuring human IL-11 in research samples?

Several methods exist for quantifying human IL-11, with HTRF (Homogeneous Time-Resolved Fluorescence) technology offering advantages over traditional ELISA for many research applications. The HTRF human IL-11 detection kit provides a streamlined approach for quantifying IL-11 release into cell supernatants with minimal sample volume requirements (16 μL) . This homogeneous add-and-read assay allows direct dispensing of cell supernatant samples or standards into assay plates for detection by HTRF reagents. The antibodies labeled with HTRF donor and acceptor are pre-mixed and added in a single step, simplifying the procedure. For data analysis, the 4 Parameter Logistic (4PL) curve is recommended, as it enables accurate measurement across a wider concentration range than linear analysis, making it well-suited for analyzing biological systems like cytokine release .

How should researchers design experiments to study IL-11 function in cell and tissue models?

When designing experiments to study IL-11 function, researchers must carefully consider several critical factors that have historically led to misinterpretations. First, species-specificity is paramount - researchers should use species-matched recombinant IL-11 (e.g., human IL-11 for human cells, mouse IL-11 for mouse models) to avoid confounding results. Early literature (1995-2015) extensively reported recombinant human IL-11 (rhIL-11) as protective in mouse models of disease, but these experiments unwittingly represented loss-of-function rather than gain-of-function studies due to inhibition of endogenous mouse IL-11 signaling .
Experiments should include appropriate controls that account for potential cross-species interactions. For in vitro studies, primary cells rather than immortalized cell lines often provide more physiologically relevant responses. When measuring IL-11 effects, researchers should assess multiple downstream signaling pathways, including JAK/STAT3, ERK/P90RSK, LKB1/mTOR, and GSK3β/SNAI1, as the relative contribution of each pathway may vary by cell type and experimental condition .

What evidence prompted the paradigm shift in understanding IL-11 function?

The paradigm shift in IL-11 biology stemmed from several key discoveries that contradicted decades of previous understanding. Until the mid-2010s, IL-11 was widely considered anti-fibrotic, anti-inflammatory, and pro-regenerative based on numerous studies using recombinant human IL-11 (rhIL-11) in murine disease models. These studies consistently showed that rhIL-11 protected against liver damage, promoted liver regeneration, reduced kidney inflammation, protected against arthritis, reduced colitis, and limited cardiac fibrosis .
The shift began in 2016 when researchers identified IL-11 as the major transcriptional target of TGFβ in primary cultures of human heart fibroblasts. Contrary to expectations based on prior literature, they discovered that IL-11 actually activated fibrogenic protein translation in human fibroblasts, promoting fibrosis. Furthermore, when species-matched recombinant mouse IL-11 (rmIL-11) was injected into mice, or when rmIL-11 was transgenically expressed in mouse fibroblasts, it caused heart and kidney fibrosis and cardiorenal failure . This revelation led to the understanding that earlier studies using rhIL-11 in mice were unknowingly conducting loss-of-function rather than gain-of-function experiments, as the human protein was likely inhibiting endogenous mouse IL-11 function through competition for receptor binding without proper activation .

How do we reconcile contradictory findings about IL-11 in historical versus contemporary research?

• Cell-type specific responses

• Concentration-dependent effects

• Acute versus chronic exposure

• The specific disease context and inflammatory microenvironment

• Potential differences in signal transduction pathways engaged

What is the potential of IL-11 as a therapeutic target?

• Anti-IL-11 antibodies

• IL-11 receptor antagonists

• Small molecule inhibitors of downstream IL-11 signaling pathways

• Genetic approaches to downregulate IL-11 expression
  Each approach presents different advantages and challenges regarding specificity, delivery, and potential side effects that require careful consideration in translational research .

How does IL-11 contribute to cardiac fibrosis in experimental models?

IL-11 plays a significant role in cardiac fibrosis, with experimental models providing critical insights into its mechanisms. Studies focusing on the question "Does IL-11 have any influence on cardiac fibrosis?" have utilized rodent models of cardiac fibrosis with various treatment interventions targeting IL-11 . These experiments typically compare IL-11 modulation (either through genetic knockout or pharmacological intervention) against control conditions to assess effects on cardiac remodeling. The current understanding indicates that IL-11 promotes cardiac fibrosis through several mechanisms:

• Activation of fibroblasts to myofibroblasts, enhancing extracellular matrix production

• Promotion of fibrogenic protein translation in cardiac fibroblasts

• Signaling through JAK/STAT3 and other pathways to drive pro-fibrotic gene expression

• Enhancement of inflammatory processes that contribute to fibrosis
  This understanding represents a complete reversal from earlier literature, which incorrectly suggested IL-11 was anti-fibrotic in the heart. Recent work has clarified that IL-11 is in fact a central mediator in cardiac fibrotic processes, making it a potential therapeutic target for heart failure and other conditions characterized by pathological cardiac remodeling .
  Experimental approaches studying IL-11 in cardiac fibrosis include:

• Genetic knockout models (IL-11 or IL-11RA deficient mice)

• Transgenic overexpression models

• Pharmacological inhibition (antibodies, receptor antagonists)

• Various cardiac injury models (pressure overload, myocardial infarction, etc.)
  Each model provides complementary insights into how IL-11 influences cardiac structural changes, function, and long-term outcomes .

What are the key differences between human and mouse IL-11 biology?

Understanding the species-specific differences in IL-11 biology is crucial for proper experimental design and interpretation. Several key differences between human and mouse IL-11 systems have been identified:

• Receptor Structure and Specificity: The human IL-11 receptor (IL-11RA) and mouse receptor (Il11ra1) share homology but have structural differences. Human IL-11RA exists in two isoforms (IL-11Rα1 with a short cytoplasmic domain and IL-11Rα2 lacking this domain), while the murine genome contains both an IL-11Rα1 gene (with 14 exons compared to human's 12) and a second IL-11Rα-like locus (IL-11Rα2) with sequence homology to exons 2-13 of IL-11Rα1 .

• Cross-Species Compatibility: Human IL-11 (rhIL-11) has limited activity on mouse Il11ra1 and may actually inhibit endogenous mouse Il11 signaling through competitive binding without proper activation. This explains why many early studies using rhIL-11 in mice showed protective effects that were misinterpreted as gain-of-function when they were actually demonstrating loss-of-function .

• Genomic Organization: The human IL-11Rα1 gene consists of 12 exons and 12 introns within a 9-kb genomic region located on chromosome 9 band 9p13. In contrast, the murine IL-11Rα gene contains 14 exons and shows evidence of developmentally regulated alternative first exon usage .

• Expression Patterns: IL-11RA and IL-6R (a related cytokine receptor) show different expression patterns between species. Generally, IL-11RA is most highly expressed on stromal cells (e.g., adipocytes, fibroblasts, vascular smooth muscle cells), whereas IL-6R is more strongly expressed on immune cells (e.g., monocytes) .
  These differences underscore the importance of using species-matched reagents in experimental studies and caution against direct extrapolation between mouse models and human biology without proper validation.

Comparison Table of IL-11 Functions: Old vs. New Understanding