Cytokines in Staphylococcus aureus arthritis. For better for worse

Sammanfattning: Septic arthritis is an inflammatory condition in joints caused by in situ residing bacteria accompanied by a septic reaction. Bacteria reach their target via the blood stream and the major human pathogen is Staphylococcus aureus. The local and systemic inflammation often results in irreversible cartilage and bone necrosis or, in the worst case, a lethal circulatory collapse.The regulation of immune responses following S. aureus infection is to a great extent mediated by signal proteins, called cytokines. To examine the importance of certain cytokines in this condition, S. aureus were intravenously inoculated into cytokine gene knockout mice and their respective controls. Interleukin-4 (IL-4) and IL-12 gene targeted mice were studied to analyse the role of these cytokines, known to direct T cell responses towards type2 or type1, in S. aureus arthritis. Further, the role of tumor necrosis factor (TNF) alone and the combined impact of TNF and lymphotoxin-a (LTa) were investigated, since upregulation of TNF and LTa during S. aureus arthritis and sepsis occurs.The impact of IL-4 for the outcome of S. aureus arthritis depends on the genetic background of the host. A detrimental effect of IL-4 is seen in C57BL/6 mice, regarding both arthritis and death, in part due to decreased intracellular (IC) killing of staphylococci. Decreased IC killing of bacteria is seen also in macrophages derived from 129Sv mice, but in those mice IL-4 provides protection from septic death, probably by down-regulation of inflammatory responses. IL-12 production is protective in S. aureus arthritis with regard to both survival and staphylococcal clearance, possibly by induction of interferon-gamma (IFN-g). TNF/LTa protect mice from uncontrolled staphylococcal growth and septic death, showing an important role in upregulation of phagocytic activity. On the other hand production of TNF/LTa leads to increased severity of arthritis. In Staphylococcus aureus arthritis, TNF, TNF/LTa and IL-12 attract and activate phagocytes, being directly or indirectly beneficial for reducing bacterial load, while IL-4, down-regulates the killing of bacteria and thereby provides a favourable milieu for survival of staphylococci. Enhanced capacity of the host to reduce the numbers of staphylococci results in decreased frequency of arthritis, as shown in IL-4-deficient C57BL/6 mice. However, even if the ability to kill staphylococci is increased by certain cytokines joint inflammation may be worsened as in the case of TNF. With regard to survival, the capacity to kill bacteria is of importance, being positively correlated with survival, as shown in TNF/LTa-, IL-12- and IL-4-deficient C57BL/6 mice. IL-4 down-regulates phagocytic killing of staphylococci also in another genetic background, but in these IL-4-deficient mice the absence of IL-4 is fatal. Though basic properties attributed to a cytokine in one genetic background might be true also in a second one, the final outcome of disease depends on the milieu in which they act. The results, if applicable in human S. aureus arthritis, suggest that interactions with cytokines may be used to: (I) increase phagocytic activity, and/or (II) down-regulate an overheated immune system, i.e. to decrease destruction of joints and/or prevent septic shock.

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