Cytokine Response to Injury

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Tumor Necrosis Factor

Following acute injury or during infections, TNF-alpha is among the earliest and most potent mediators of subsequent host responses. The primary sources of TNF-alpha synthesis include monocytes/macrophages and T cells, which are abundant in the peritoneum and splanchnic tissues. Furthermore, Kupffer cells represent the single largest concentrated population of macrophages in the human body. Therefore, surgical or traumatic injuries to the abdominal viscera undoubtedly have profound influence on the generation of inflammatory mediators and homeostatic responses such as acute phase protein production. 

Although the half-life of TNF-alpha is less than 20 minutes, this brief appearance is sufficient to evoke marked metabolic and hemodynamic changes and activate mediators distally in the cytokine cascade. TNF-alpha is also a major inducer of muscle catabolism and cachexia during stress by shunting available amino acids to the hepatic circulation as fuel substrates. Other functions of TNF-alpha include coagulation activation, promoting the expression or release of adhesion molecules, prostaglandin E2 , platelet-activating factor (PAF), glucocorticoids, and eicosanoids.

During sepsis, cytokines (IL-1, IL-2, TNF) released by lymphocytes and macrophages contribute to catabolism of muscle and adipose tissue and amplify the neurohormonal response to antecedent trauma.

Soluble (i.e., circulating) TNF receptors (sTNFRs) are proteolytically cleaved extracellular domains of membrane-associated TNFRs that are elevated and readily detectable in acute inflammation. sTNFRs retain their affinity for the binding of TNF-alpha and therefore compete with the cellular receptors for the binding of free TNF-alpha. This potentially represents an endogenous counterregulatory response to excessive systemic TNF-alpha activity. However, it should be noted that the functional biology of sTNFRs may not be limited to TNF-alpha antagonism, but may also serve as a carrier (e.g., transporter) or as a storage pool of bioactive TNF-alpha in the circulation.

Board Review Questions


1.  A 35-year-old male develops a fever of 38.9°C 24 hours following a motor vehicle accident in which he sustained multiple lower extremity fractures. This febrile response stems from which of the following mediators?

A. IL-1

B. IL-2

C. IFN-alpha

D. IL-10

E. IL-4

2.  TNF-alpha features prominently in all of the following except:

A. inhibition of the coagulation cascade

B. neutrophil chemotaxis

C. apoptosis

D. angiogenesis

E. protection against intracellular bacteria

3.  Choose the one best response to this question.

An example of an anti-inflammatory cytokine is

A. IL-2

B. IFN-gamma

C. Lymphotoxin-alpha (LT-alpha)

D. IL-4

E. TNF-alpha


1. The correct answer is A. IL-1

2. The correct answer is A. inhibition of the coagulation cascade

3. The correct answer is D. IL-4

Go to the profile of Gerard Doherty

Gerard Doherty

Moseley Professor of Surgery, Harvard Medical School, Surgeon-in-Chief, Brigham Health & Dana-Farber Cancer Institute

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