62 5 ART for Anti-inflammation
insufficient to induce the classic arthritic lesions in mice. Some authors thought
that anti-CII reactivity might be a consequence of inflammation rather than the
cause (Courtenay et al. 1980 ). This is the reason why so many kinds of autobodies
can be detected in the blood of RA patients or experimental arthritic rodents, such
as those against citrullinated proteins, glucose-6-phosphate isomerase, integrin,
and fibrin, etc. (McDevitt 2000 ; Wilder 2002 ; Humby et al. 2009 ). So we assumed
that CII is likely dispensable for modeling RA in mice. Indeed, we successfully
induced acute arthritis in mice by intra-articular injection with CFA alone instead
of CII-CFA. Therefore, any immune activators including autoantigens and bacte-
ria, either live or dead, can evoke the immune responses and make the inflamma-
tory lesions by provoking the NO-driven hypoxia.
The mucosal response to an enteric infection includes the production of che-
moattractant cytokines (chemokines), anti-inflammatory cytokines, and proinflam-
matory cytokines, in which TNFα is an important proinflammatory cytokine that
amplifies the epithelial immune response to the bacterial infection (Eckmann and
Kagnoff 2005 ). TNFα, IL-1β, and other proinflammatory cytokines can upregulate
iNOS in chondrocytes and synovial cells of osteoarthritis (Abramson 2004 ). In
the present study, we observed a global activation of chemokines, cytokines, and
corresponding receptors in BIA and CIA mice, which drives a complicated and
chronic inflammatory process (Cejka et al. 2010 ). The unexpected outcome that
TNFα is downregulated in CIA mice seems puzzling, but it is most likely because
the attenuation of immune responses to CII-CFA after several weeks of immuniza-
tion. In fact, sampling for cytokine chip profiling was carried out after 28 days of
modeling.
Although the implication of NO in the pathogenesis of experimental arthritis
was poorly understood, CII-CFA-triggered NO burst has been noticed in CIA mice
(Cannon et al. 1996 ). We have observed the formation of double NO peaks after
primary challenging and boosting with CII-CFA, and also noticed a stable NO
level higher than the control during daily live bacterial feeding. Albeit in distinct
manners, either CII-CFA or bacteria can provoke NO production, permanently or
transiently, in BIA and CIA mice. Surprisingly, we also found that cotreatment
by CII-CFA with bacteria allows a global downregulation of proinflammatory
cytokines, suggesting the bacteria-conferred suppression to CII-CFA-activated
immune responses. In consistence with our findings, other authors have previously
reported that Schistosoma japonicum infection can significantly attenuate the clini-
cal signs, reduce the histological damages, alter the humoral immune responses,
and inhibit the splenocyte proliferation in CIA mice (Song et al. 2011 ).
Additionally, immunosuppression by bacteria has been addressed in a recently
published review (Kelly et al. 2012 ). Because arthritic development is mostly
dependent on the systemic immune activation, immunosuppression can, of course,
alleviate the inflammatory arthritis. RAP is a well-known immunosuppressant that
reduces pannus formation, cartilage erosion, and joint damage in rats with adju-
vant-induced arthritis (Teachey et al. 2009 ). ART also plays an antiarthritic role
in CIA mice (Wang et al. 2008 ). Even though the pharmacological mechanisms
of RAP and ART as arthritic therapeutics are thought to be multifaceted, it is