2.1.4 The TOLL receptor
Toll-like receptor (TLR) is a molecular pattern associated with the recognition of specific pathogens. Toll-like receptor-2 recognizes multiple microbial components of Gram-positive bacteria and TLR4 is required for the lipopolysaccharide response, an external component of Gram-negative bacterial membranes52.TLR4 activation has been associated with neonatal lung inflammation53,54. Studies showed that caffeine had no significant effect on TLR2 and 4 in normal neonatal rat lung tissue, but increased TLR9 expression, limited TLR4 expansion, inhibited pro-inflammatory cytokine production, and reduced the severity of BPD55. In addition, Ren et al.found that caffeine may inhibit the TLR-mediated inflammatory cascade response in macrophages by suppressing calcium mobilization56. It was also demonstrated in human monocytes that high concentrations of caffeine (200µM) upregulated TLR4 to promote inflammation, while 50 and 100µM of caffeine downregulated TLR1 and TLR2 expression and was able to reduce TNF-α levels;this may be related to the reduced incidence of BPD by caffeine57.