The findings suggest that the cytokine response of blood monocytes in CRC patients differs from that of healthy individuals, with TNF-α secretion becoming exhausted and IL-1β secretion remaining elevated. Observable differences in cytokine secretion can be explained by significant differences in the key properties of TNF-a and IL-1b. Specifically, TNF-a and IL-1b have different functions in the inflammatory response - TNF-a is more involved in the acute phase of inflammation, inducing a reaction in endothelial cells, increasing vascular permeability, enhancing the expression of adhesion molecules and other cytokines. In addition, TNF-a can influence cell survival, depending on the activated mechanism - including initiating apoptosis through Fas receptors. IL-1b is also a pro-inflammatory cytokine, mainly affecting immune cells, including T-cell activation and stimulating the production of other cytokines. The production and secretion of TNF-a and IL-1b by cells occur through different mechanisms. TNF-a expression is mainly activated through the NF-κB (nuclear factor kappa B) signaling pathway, while IL-1b expression is characterized by activation through the NLRP3 (NOD-like receptor family, pyrin domain-containing 3) inflammasome pathway. The secretion kinetics also differ: TNF-a rapidly reaches a peak of 1–2 hours after exposure to LPS due to the mechanism of rapid cleavage and transition to a soluble form located in type II transmembrane protein (pro-TNF) in cell membranes, with the help of the tumor necrosis factor-alpha converting enzyme (TACE) enzyme. The secretion process of IL-1b is longer, reaching a peak at 4–6 hours and requiring the initiation of interleukin precursor and inflammasome formation. Another difference in cytokine action mechanism is that the effect of TNF-a on the cell depends on the type of receptor with which it binds - TNFR1, TNFR2, Fas, while the main receptor of IL-1b is IL-1R [6–8].
Clearly, these two cytokines can play completely different roles in the inflammatory response. Based on the research results, it can be assumed that in colorectal cancer, the functions associated with TNF-a secretion by monocytes change, which fits the concept of colorectal cancer as a disease closely associated with inflammation.
Several hypotheses requiring verification could help explain the abnormal secretion of TNF-α by monocytes in patients with CRC, and they are as follows:
Acquired immune tolerance of monocytes may serve as a mechanism to protect tumors from immune attack [9]. Although IL-1β secretion in patients with colorectal cancer is even higher than in the comparison group, a more comprehensive panel of cytokines needs to be experimentally determined to complete the picture.
Studying changes in the function of key signaling pathways in monocytes, such as NF-κB or MAPK, may provide an answer to the observed phenomenon [10]. Identifying changes in the activation of these pathways will help better understand the nature of the abnormal decrease in TNF-α secretion.
Investigating the influence of the tumor microenvironment may also play a role [11]. The tumor stroma is an active regulator of inflammation and immune response. Soluble and exosomal factors from tumor cells and/or the tumor microenvironment may affect the reduced re-release of TNF-α by monocytes.
Cell depletion of monocytes in patients with colorectal cancer may be another cause [12]. Monocytes release TNF-α upon the first stimulation but do not restore the necessary cellular resources for subsequent secretion.
In addition, the development of colorectal cancer is accompanied by a disturbance in the composition of the intestinal microbiota and permeability of the intestinal wall to gut biota [13]. Interaction of monocytes through a disrupted barrier with the gut microbiota and its metabolites may lead to exhaustion or blockade of TNF-α secretion upon subsequent interaction with LPS.