Table 1.

Known cytokines' capacity to induce biological changes in neutrophils in RA.

Cytokines/blockade	Human RA or mouse model	Expression	Migration or recruitment	Apoptosis or survival	NET formation	Outcome
TNF-α	Human RA	↑ in serum and synovial fluid [13, 18, 19]	↑ in vitro [11]	Promote or delayed apoptosis In vitro [27]	↑ in vitro [13]
Blockade of TNF-α	Human RA	—	↓in vivo [18]	Antiapoptotic Mcl-1 ↑ and proapoptotic caspase-9 ↓ [57]	↓ in vitro [13, 73]	Improved [73, 98]
TNFR−/−	Collagen Ab and LPS-inducedarthritis model	—	↓ in vivo [52]	—	—	Improved [52]
IL-6	Human RA	↑ in serum and synovial fluid [19–21]	No effect in vitro [21]	No effect in vitro [21], delayed apoptosis in vitro [27]	↑ in vitro [73] ↑ in vitro∗ [75]	—
Blockade of IL-6	Human RA	—	—	No effect in vivo and ex vivo [21]	↓ in vivo and in vitro [73, 76]	Improved [99]
IL-17a	AIA mouse model and human RA	↑ in the joint [22, 23]	↑ in vivo [22]	—	↑ in vitro [13]
Adenoviral vectors with IL-17	IC-mediated arthritis mouse model	—	↑ in vivo [38]	—	—	Deteriorated [38]
Anti-IL-17 antibody administration	CIA model	—	↓ in vivo [44]	—	↓ in vitro [13]	Improved [44]
IL-23	AIA mouse model and human RA	↑ in joint [22, 24]	↑ in vivo [22]	—	—	—
IL-22	AIA mouse model and human RA	↑ in synovial tissue [25, 26]	↑ in vivo [25]	—	—	—
Block IL-22 or IL-22−/−	AIA mouse model	—	↓ in vivo [25]	—	—	Improved [25]
rmIL-22 administration	Normal mice	—	↑ in vivo [25]	—	—	Deteriorated [25]
IL-1β	Human RA and AIA mouse model	↑ in synovial fluid [19]	↑ in vitro [25]	Delayed apoptosis in vitro∗ [62]	↑ in vitro∗ [81–83]	—
IL-1R−/− or IL-1R antagonist	Collagen Ab and LPS-inducedarthritis model	—	↓ in vivo [52]	—	↓ in vitro∗ [82, 83]	Improved [52]
IL-8	Arthritis rabbit model and human RA	↑ in synovial fluid [19, 27]	↑ in vivo [39], ↑ in vitro [58]	No effect in vitro [27]	↑ in vitro [13]	—
Blockade of IL-8	Arthritis rabbit model	—	↓ in vivo [39]	—	—	Improved [39]
IL-10	Human RA	↑ in synovial fluid [19]	—	—	↑ in vitro∗ [100]	—
IFN-γ	Human RA	↑ in synovial fluid [19]	—	Delayed apoptosis in vitro [58]	↑ in vitro∗ [79]	—
IFN-γ−/−	AIA, CIA model	—	↑ in vivo [43, 44]	—	—	Deteriorated [43, 44]
GM-CSF	Human RA	↑ released by RAFLS in vitro [28], ↑ in serum and synovial fluid [18, 29, 30]	—	Survival ↑ [28], delayed apoptosis in vitro [27, 57, 58]	No effect in vitro [13]	—
Blockade of GM-CSF	CIA	—	↓ neutrophils in the joint [48]	—	—	Improved [48]
GM-CSF−/−	K/BxN serum transfer arthritis	—	↓ neutrophils in the joint [48]	—	—	Improved [48]
G-CSF	Human RA	↑ in serum and synovial fluid [30, 31]	—	—	↑ in vitro∗ [101]	—
rhG-CSF	CIA	↑ serum G-CSF [51]	↑ in vivo [51]	—	—	Deteriorated [51]
G-CSF−/−	CIA	—	↓ in vivo [51]	—	—	Improved [51]
mAb to G-CSF receptor	Collagen Ab-induced arthritis model	—	↓ in vivo [47]	—	—	Improved [47]
IL-9	Human RA	↑ in serum and synovial fluid [32, 33]	—	Delayed apoptosis [32]	↑ in vitro∗ [85]	—
IL-15	Human RA	↑ in synovial fluid [34]	↑ in vivo [45]	Delayed apoptosis in vitro [27]	↑ in vitro∗ [100]
IL-18	Human RA	↑ in serum, synovial tissue and fluid [35]	↑ in vivo [53]	No effect in vitro [59]	↑ in vitro∗ [100]
IL-33	mBSA-immunized mouse model	↑ mRNA expression [11]	↑ in vivo [11]	—	↑ in vitro∗ [86]
rmIL-33	rmIL-33 local injection	—	↑ in vivo [11]	—	—	Deteriorated [11]
Blockade of IL-33	mBSA-immunized mouse model	—	↓ in vivo [11]	—	—	Improved [11]
IL-37	Human RA	↑ in serum and synovial fluid [36]	—	—	—
IL-37 administration	CIA and streptococcal cell wall fragments induced arthritis	—	↓ in vivo [54]	—	—	Improved [54, 102]

RA: rheumatoid arthritis, NETs: neutrophil extracellular traps, TNF-α: tumor necrosis factor-alpha, Mcl-1: myeloid cell leukemia-1, TNFR: tumor necrosis factor receptor, Ab: antibody, LPS: lipopolysaccharide, IL: interleukin, AIA: antigen-induced arthritis, IC: immune complex, rmIL-22: recombinant murine interleukin 22, IL-1R: interleukin 1 receptor, IFN-γ: interferon gamma, CIA: collagen-induced arthritis, GM-CSF: granulocyte/macrophage colony-stimulating factor, RAFLS: rheumatoid arthritis synovial fibroblasts, G-CSF: granulocyte colony-stimulating factor, mAb: monoclonal antibody, mBSA: methylated bovine serum albumin, rmIL-33: recombinant murine interleukin 33, rhIL-37: recombinant human interleukin 37. ^∗ is found in other inflammatory diseases or healthy individuals, but not RA