**3. Inflammation and FA**

Inflammation is a biological process orchestrated mainly by myeloid cells and accompanied by infection or phagocytosis (Balwill *et al.,* 2001). Increased oxidative stress in FA patients may be the result of an increased burden of endogenously produced oxidants as well as increased amounts of ROS generated by various inflammatory cytokines. Many studies indicate a correlation between elevated circulating pro-inflammatory cytokines and anemia in patients with leukemia-related BM diseases (Hakim *et al.,* 1993), but direct evidence for the mechanistic link between inflammation and BMF or leukemia is lacking.

There is evidence showing that patients with FA have abnormally high levels of TNF- (Fagerlie *et al.,* 2001; Fiers *et al.,* 1999; Freie *et al.,* 2003), which is a major mediator of inflammation and ROS production (Liu *et al.,* 2003; Lohrum *et al.,* 1999). Inappropriate induction or activation of TNF-signaling has been implicated in the pathogenesis of numerous common diseases such as arthritis, heart attacks, and cancer (Ekbom *et al.,* 1990; Jonsson *et al.,* 2005; Mantovani *et al.,* 2002; Marx *et al.,* 2004). It is conceivable that the presence of TNF- and increased oxidative stress in FA BM may account for profound physiologic changes, including the development of BMF and progression to leukemia.

Similar to TNF-, IL-1 and IL-6 are also well-known pro-inflammatory cytokines with a wide range of biological activities in immune regulation, hematopoiesis, inflammation and oncogenesis (Ibanez *et al.,* 2009). It has been demonstrated that IL-1 is overexpressed in FA-A patients (de Cremoux *et al.,* 1996). The elevated levels of IL-1*β* were completely reverted by complementation of functional FANCA into FA-A lymphocytes. In addition, the constitutive activation of the PI3K-Akt pathway in FA cells upregulates the expression of IL-1*β* through an NF-*κ*B independent mechanism and this overproduction activates the proliferation of tumour cells (Ibanez *et al.,* 2009). IL-6 is the chief stimulator of the production of most acute phase proteins (Scheller *et al.,* 2011), whereas the other implicated cytokines influence subgroups of acute phase proteins. Recent studies demonstratethe presence of a defect in IL-6 production in FA patients (Coussens *et al.,* 2002; Cumming *et al.,* 1996), suggesting that this cytokine may partly be responsible for pancytopenia associated with BMF, the major clinical feature of FA, in FA patients. In addition, it has been reported that *Fancc-/-* HSC/P cells had altered growth and apoptosis responses to combinations of stimulatory cytokines, most dramatically in response to a combination of factors that included interleukin-3 (IL-3) and IL-6 (Aubé *et al.,* 2002).
