Circadian characteristics of permissive and suppressive effects of cortisol and their role in homeostasis and the acute inflammatory response.

In this work we explore a semi-mechanistic model that considers cortisol's permissive and suppressive effects through the regulation of cytokine receptors and cytokines respectively. Our model reveals the proactive role of cortisol during the resting period and its reactive character during the body's activity phase. Administration of an acute LPS dose during the night, when cortisol's permissive effects are higher than suppressive, leads to increased cytokine levels compared to LPS administration at morning when cortisol's suppressive effects are higher.

Mathematical modeling of light-mediated HPA axis activity and downstream implications on the entrainment of peripheral clock genes.

In this work we propose a semimechanistic model that describes the photic signal transduction to the hypothalamic-pituitary-adrenal (HPA) axis that ultimately regulates the synchronization of peripheral clock genes (PCGs). Our HPA axis model predicts that photic stimulation induces a type-1 phase response curve to cortisol's profile with increased cortisol sensitivity to light exposure in its rising phase, as well as the shortening of cortisol's period as constant light increases (Aschoff's first rule). Furthermore, our model provides insight into cortisol's phase and amplitude dependence on photoperiods and reveals that cortisol maintains highest amplitude variability when it is entrained by a balanced schedule of light and dark periods.

APOε4 is associated with enhanced in vivo innate immune responses in human subjects.

Background: The genetic determinants of the human innate immune response are poorly understood. Apolipoprotein (Apo) E, a lipid-trafficking protein that affects inflammation, has well-described wild-type (ε3) and disease-associated (ε2 and ε4) alleles, but its connection to human innate immunity is undefined.

Objective: We sought to define the relationship of APOε4 to the human innate immune response.

A genomic storm in critically injured humans.

Human survival from injury requires an appropriate inflammatory and immune response. We describe the circulating leukocyte transcriptome after severe trauma and burn injury, as well as in healthy subjects receiving low-dose bacterial endotoxin, and show that these severe stresses produce a global reprioritization affecting >80% of the cellular functions and pathways, a truly unexpected "genomic storm." In severe blunt trauma, the early leukocyte genomic response is consistent with simultaneously increased expression of genes involved in the systemic inflammatory, innate immune, and compensatory antiinflammatory responses, as well as in the suppression of genes involved in adaptive immunity.

Pulsatile glucocorticoid secretion: origins and downstream effects.

Glucocorticoids are steroid hormones which, among other functions, exert an antiinflammatory effect. Endogenous glucocorticoids are normally secreted by the adrenal gland in discrete bursts. It is becoming increasingly evident that this pulsatile secretion pattern, leading to ultradian rhythms of plasma glucocorticoid levels, may have important downstream regulatory effects on glucocorticoid-responsive genes.

Modeling autonomic regulation of cardiac function and heart rate variability in human endotoxemia.

Heart rate variability (HRV), the quantification of beat-to-beat variability, has been studied as a potential prognostic marker in inflammatory diseases such as sepsis. HRV normally reflects significant levels of variability in homeostasis, which can be lost under stress. Much effort has been placed in interpreting HRV from the perspective of quantitatively understanding how stressors alter HRV dynamics, but the molecular and cellular mechanisms that give rise to both homeostatic HRV and changes in HRV have received less focus.

Computational identification of transcriptional regulators in human endotoxemia.

One of the great challenges in the post-genomic era is to decipher the underlying principles governing the dynamics of biological responses. As modulating gene expression levels is among the key regulatory responses of an organism to changes in its environment, identifying biologically relevant transcriptional regulators and their putative regulatory interactions with target genes is an essential step towards studying the complex dynamics of transcriptional regulation. We present an analysis that integrates various computational and biological aspects to explore the transcriptional regulation of systemic inflammatory responses through a human endotoxemia model.

A dual negative regulation model of Toll-like receptor 4 signaling for endotoxin preconditioning in human endotoxemia.

We discuss a model illustrating how the outcome of repeated endotoxin administration experiments can emerge as a natural consequence of the tightly regulated signaling pathways and also highlight the importance of a dual negative feedback regulation including PI3K/Akt and IRAK-M (IRAK3). We identify the relative time scales of the onset and the magnitude of the stimulus as key determinants of outcome in repeated administration experiments. The results of our simulations involve potentiated response, tolerance, and protective tolerance.

Agent-based modeling of endotoxin-induced acute inflammatory response in human blood leukocytes.

Background: Inflammation is a highly complex biological response evoked by many stimuli. A persistent challenge in modeling this dynamic process has been the (nonlinear) nature of the response that precludes the single-variable assumption. Systems-based approaches offer a promising possibility for understanding inflammation in its homeostatic context.