Shinichiro Fujii and Michael T Lotze Abstract

IL-10 is a dichotomous functional cytokine. It has characteristics of being both an immunosuppressive and immunostimulatory cytokine. In the setting of many infectious diseases including some viral infections, IL-10 administration prevents infected mice from progressing. IL-10 activates the cytolytic function of NK cells as well as that mediated by activated/memory CD8+T cells. In a second stage following infection, IL-10 released from host cells often protects the host from secondary hyperinflammation, capable of damaging tissues, whereas endogenous IL-10 often imposes a suppressive function on CD4+ T cells and antigen presenting cells. The IL-10 effects, modulating hyperinflammation can also induce regulatory T cells. In contrast, IL-10 production generated by or stimulated directly by some bacteria or protozoa infected DC may induce regulatory T cells, thereby helping microbes to aggressively invade host tissues. Indeed, IL-10-/- mice are protected from some infectious diseases. In the setting of tumor immunobiology, IL-10 expression appears to promote rejection of most experimental tumors. Thus, IL-10 release regulates innate immune mechanisms important for controlling microbes and playing a role in the chronic inflammatory response associated with tumorigenesis or secondary host defenses limiting progression of infection and host tissue damage.

The release of IL-10 during the acute or chronic inflammatory response regulates innate immune mechanisms following infection and specific immune responses to intracellular bacteria, fungi or protozoa. Systemic inflammatory responses occur after local infections including focal inflammation associated with cellulitis or pneumonia, systemic infections/sepsis, or non-infectious events including severe trauma, or burns, associated with pro-inflammatory cytokine release. Following infection, tissue damage induced directly by bacteria as well as the destruction mediated by the potent antimicrobial responses of the host-itself may cause significant damage to tissues, resulting in necrosis and loss of function. Such tissue damage leads to early cellular infiltration, progressing to granuloma formation during chronic-infection with resultant fibrosis and replacement of normal tissue.

During systemic inflammation, pro-inflammatory cytokines including TNF-a, IL-1, IL-18, IFN-y and IL-12 play a central role in regulating the initiation and propagation of these events.1,2 Release of such cytokines in patients infected with T. gondii, P. chaubudi, or certain strains of T.cruzi may cause substantial morbidity. The production of such pro-inflammatory cytokines by host cells stimulated by so called pattern recognition molecules capable of "sensing" bacterial or viral products is crucial to initiation of the innate and adaptive immune responses to infection. 1 These cytokines enhance the bactericidal capacity of phagocytes, recruiting additional innate cell populations to sites of infection and promote dendritic cell (DC) maturation which are capable of directing the ensuing specific immune response to the invading microbes.

Some bacterial pathogens have evolved mechanisms for modulating cytokine production by host cells, which modifies the host's subsequent immune response. Therefore, it is important to understand the suppressive or regulatory factors involved with inflammation following the inflammation associated with infection, sometimes paradoxically resulting in a state of

Interleukin-10, edited by Francesco M. Marincola. ©2006

immunosuppression or immunoparalysis. Following instances of severe inflammation, IL-10 may play a critical role, helping to modulate the pathological consequences of local and systemic inflammatory responses. Infection models using IL-10-/- mice models suggest that the resultant immunopathology is apparently dependent upon Th1 or Tc1 type- T cell induction. IL-10 also inhibits Th2-mediated granulomas and fibrosis as secondary inflammatory effects in mouse models of schistomiasis as well as the immunopathology associated with the Th1 response.3-5 To understand the interaction between the innate and adaptive immune responses against most pathogens, evaluation of the critical regulatory role played by IL-10 is essential.

The release of IL-10 may inhibit some antimicrobial responses during the initial inflammatory stage, but rescue the host from hyperinflammation or tissue damage elicited by host defense mechanisms following infection. In this chapter, we will discuss the role of IL-10 in regulating the response to infectious diseases and host defense by its ability to modulate innate immune mechanisms.

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