The ‘cytokine profile’: a code for sepsis

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Sepsis – the most common cause of death in hospitalized patients – affects over 18 million people worldwide and has an expected 1% increase of incidence per year. Recent clinical trials indicate that therapeutic approaches effective in diseases with similar pathogenesis have a modest effect against sepsis. Although the reason for this failure remains controversial, recent studies provide new insights and promising experimental strategies. We propose that the current definition of sepsis is too broad and encompasses heterogeneous groups of patients suffering similar, but different, syndromes that are historically grouped under the general diagnosis of sepsis. Future clinical trials might define patient populations and therapeutic strategies according to the profile of expression of cytokines.

Introduction

Severe sepsis is the leading cause of death in intensive care units and accounts for 9.3% of overall deaths in the United States annually 1, 2, 3, 4. Sepsis is the third leading cause of death in developed societies, equaling the number of fatalities from acute myocardial infarction 3, 4. Despite the use of antibiotics, severe sepsis remains a major cause of death, in part because antibiotics cannot control systemic inflammation and severe sepsis is not exclusively produced by infections. Infection, trauma, ischemia and severe injury contribute to the pathogenesis of severe sepsis, which is characterized by an overwhelming production of proinflammatory cytokines, such as tumor necrosis factor (TNF), interleukin (IL)-1β and high-mobility group box (HMGB)-1 (Figure 1). These cytokines trigger a beneficial inflammatory response that promotes local coagulation to confine tissue damage. However, the excessive production of these proinflammatory cytokines can be even more dangerous than the original stimulus, overcoming the normal regulation of the immune response and producing pathological inflammatory disorders 5, 6, 7, 8, 9, 10, 11, 12, 13. This is especially notable in severe sepsis, in which the excessive production of proinflammatory cytokines causes capillary leakage, tissue injury and lethal organ failure 11, 12, 13, 14, 15, 16, 17. Experimental strategies neutralizing these cytokines (monoclonal antibodies against TNF, IL-1-receptor antagonists and TNF-receptor fusion proteins) are a successful therapeutic approach against several inflammatory disorders, including rheumatoid arthritis and Crohn's disease 18, 19. However, these cytokine-based strategies have produced modest effects in clinical trials and failed to receive the approval of the Food and Drug Administration (FDA) in the US for the treatment of sepsis 20, 21, 22. Therapeutic approaches that appear effective in diseases with similar pathogenesis have failed against sepsis. Although the reason for this challenging conundrum remains controversial, we propose that the current definition of sepsis is too broad, encompassing heterogeneous groups of patients who do not necessarily have the same disorder.

Section snippets

Definition of sepsis: ‘septic shock’ is not ‘severe sepsis’

Sepsis is defined by the clinical signs of a systemic immune response to infection 23, 24. Originally, the diagnosis of sepsis required the confirmation of bacterial infection and at least two of the following clinical signs: abnormalities of body temperature (hypothermia or hyperthermia), heart rate (tachycardia), respiratory rate (tachypnea) and white blood cell count (leukocytopenia or leukocytosis). Sepsis is defined as ‘severe’ when these findings occur in association with signs of organ

TNF: a prototype mediator of septic shock

TNF is a primary mediator of the innate immune system and is crucial for the induction of a local protective immune response against infections, trauma or ischemia (Figure 2a). However, excessive TNF production can be lethal itself, because it spreads in the bloodstream and produces cardiovascular collapse 9, 10, 17. TNF is a sufficient and necessary mediator of septic shock because: (i) it is found in patients and experimental models of septic shock 9, 10; (ii) it is capable of triggering the

HMGB1: a prototype mediator of severe sepsis

HMGB1 protein has recently been identified as a late mediator of sepsis and, thus, a potential mediator of severe sepsis 32, 33. Originally described as a nuclear DNA-binding protein, HMGB1 can also be secreted into the extracellular milieu by stimulated macrophages, and extracellular HMGB1 functions as a proinflammatory cytokine that contributes to severe sepsis (Figure 2b). HMGB1 seems to be a sufficient and necessary mediator for severe sepsis because: (i) systemic HMGB1 is found in patients

The ‘cytokine code’ in sepsis

Proinflammatory cytokines represent molecular messages that code for a precise immune response against infection, trauma or injury. Similar to a molecular fingerprint, a pathological profile of cytokines production results in a characteristic constellation of clinical symptoms (Figure 3a). The characterization of this putative ‘cytokine code’ will enable the translation of a specific group of proinflammatory cytokines into a specific collection of clinical signs and symptoms and, thus, immune

Genetic determination of the cytokine profile

Caspase, a family of aspartate-specific proteases, contributes to the pathogenesis of sepsis by regulating cytokine production and apoptosis during infection and the subsequent inflammatory response 62, 63. Caspases (caspase-1, -4, -5 and 12) modulate the immune response by processing cytokine precursors, and, for example, caspase-1 mediates the cleavage of IL-1β and IL-18 64, 65. As a consequence, a genetic mutation in a single caspase can alter the pattern of production of a set of cytokines.

Concluding remarks

Immunosuppressive strategies inhibiting specific proinflammatory cytokines have shown controversial effects and have failed to obtain consistent results in similar studies of patients diagnosed with severe sepsis 21, 22, 23. By contrast, other studies indicate that different anti-immunosuppressive strategies have shown a beneficial effect in experimental models of sepsis 59, 60, 61. Activated protein C (Drotrecogin α), the only treatment for sepsis that is approved by the FDA, is used in a

Acknowledgements

We sincerely apologize to those authors whose work could not be cited. The authors are grateful for the thoughtful suggestions from Barbara Sherry and Raul Wapnir. The authors are supported by grants from the Faculty Awards Program of the North Shore Research Institute, the North Shore-LIJ GCRC, National Institute of General Medical Sciences (NIGMS) and the Defense Advanced Research Projects Agency (DARPA).

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