Update on the immunological pathway of negative regulation in acute insults and sepsis

Abstract

Sepsis with subsequent multiple organ dysfunction is a distinctly systemic inflammatory response to concealed or known infection and is a leading cause of death in intensive care units. In the initial stage of sepsis, a phase of immune activation can be evident, but a marked apoptosis-induced depletion of lymphocytes and a nonspecific anergy of immune function after severe trauma and burns might be responsible for the increased susceptibility of the host to subsequent septic complications. Recent studies indicated that negative regulation of immune function plays a pivotal role in the maintenance of peripheral homeostasis and regulation of immune responses; therefore, an understanding of the basic pathways might give rise to novel insights into the mechanisms of sepsis and immune homeostasis. This review is an attempt to provide a summary of the different pathways of negative regulation that are involved in the pathogenesis of sepsis, secondary to acute insults.

FIG. 1.

Important molecules involved in negative immune regulation. The JNK, p38, and NF-κB pathways were found to be regulated by the TIPE2 action. In addition to NF-κB signaling pathways, the biological function of HSP-specific regulatory T cells can recognize induced HSP as presented by stress cells at the site of inflammation by production of suppressive cytokines such as IL-10. Zinc finger protein A20 is found to belong to a subfamily of 14 deubiquitination enzymes, which is also involved in negative regulation associated with TLR ligation. JNK, c-Jun N-terminal kinase; I-κB, inhibitor of κB; NF-κB, nuclear factor-κb; TNF-α, tumor necrosis factor-α; TIPE2, TNF-α induced protein 8 like-2; HSP, heat shock protein; IL-10, interleukin 10; TLR, toll-like receptor; MAPK, mitogen activated protein kinase.

FIG. 2.

The impact of a negative regulator on pathogenesis and the development of sepsis, secondary to acute insults. Sepsis is a condition that results from a harmful or damaging host response to infection. The principal mechanism is that LPS is sensed via an LBP–LPS complex and then signaled through the TLR4-MD2 complex. NF-κB plays a central role in regulating the transcription of cytokines, adhesion molecules, and other mediators involved in sepsis. Recently, it has been proposed that anti-inflammatory effect of lots of important regulators during anti-bacterial response resulted from suppression of T-cell proliferation and pro-inflammatory cytokine production most likely due to inhibition of NF-κB/p50 transcription and subsequent reduction of NF-κB activity. These include TIPE2, A20, HSP, CD163, and so on. LPS, lipopolysaccharide; LBP, LPS-binding protein; AP-1, activator protein-1; MD2, myeloid differential protein 2; MyD88, Myeloid differential factor 88; IRAK, interleukin receptor associated kinase; HIF-1α, hypoxia inducible factor-1α; TRAF, TNF receptor associated factor.